Datasets:
vgainullin
/
xciting_data

Dataset card Data Studio Files
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 Community
1
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6
INTRODUCTION
0
null
null
20,047,964
pmid-9689058|pmid-10207000
The His-tagged WT and the H105A homodimers are mixed and completely unfolded with 6 M GdmCl.
null
92
40,116
0
false
null
null
The His-tagged WT and the H105A homodimers are mixed and completely unfolded with 6 M GdmCl.
true
true
true
true
true
6,922
6
INTRODUCTION
0
null
null
20,047,964
pmid-9689058|pmid-10207000
Subsequent removal of the denaturant results in formation of three species: the two initial homodimers and the heterodimer.
null
123
40,117
0
false
null
null
Subsequent removal of the denaturant results in formation of three species: the two initial homodimers and the heterodimer.
true
true
true
true
true
6,922
6
INTRODUCTION
0
null
null
20,047,964
pmid-9689058|pmid-10207000
The heterodimer with a single His-tag is separated from the homodimeric forms of BfiI lacking the His-tag or bearing two His-tags by Ni2+-chelating chromatography.
null
163
40,118
0
false
null
null
The heterodimer with a single His-tag is separated from the homodimeric forms of BfiI lacking the His-tag or bearing two His-tags by Ni2+-chelating chromatography.
true
true
true
true
true
6,922
0
DISCUSSION
1
12
[ "B12", "B13", "B13", "B16", "B26", "B27" ]
20,047,964
NA|pmid-1989886|pmid-1989882|pmid-6088516|pmid-16188275|pmid-10194386|pmid-15770420|pmid-12437341|pmid-11839309|pmid-15165852|pmid-15165852|pmid-12470949|pmid-15111055|pmid-15920477
Monomeric PLD-superfamily enzymes like human Tdp1 and PLD from Streptomyces species (12,13) are bi-lobed monomers (Figure 1A) which contain in the active site two His residues from duplicated ‘HXK’ sequence motifs located distantly in the protein chain.
[ "12", "13", "13", "16", "26", "27" ]
253
40,119
0
false
Monomeric PLD-superfamily enzymes like human Tdp1 and PLD from Streptomyces species are bi-lobed monomers (Figure 1A) which contain in the active site two His residues from duplicated ‘HXK’ sequence motifs located distantly in the protein chain.
[ "12,13" ]
Monomeric PLD-superfamily enzymes like human Tdp1 and PLD from Streptomyces species are bi-lobed monomers which contain in the active site two His residues from duplicated ‘HXK’ sequence motifs located distantly in the protein chain.
true
true
true
true
true
6,923
0
DISCUSSION
1
12
[ "B12", "B13", "B13", "B16", "B26", "B27" ]
20,047,964
NA|pmid-1989886|pmid-1989882|pmid-6088516|pmid-16188275|pmid-10194386|pmid-15770420|pmid-12437341|pmid-11839309|pmid-15165852|pmid-15165852|pmid-12470949|pmid-15111055|pmid-15920477
The active-site histidines of these enzymes are not equivalent and perform pre-defined roles in catalysis.
[ "12", "13", "13", "16", "26", "27" ]
106
40,120
0
false
The active-site histidines of these enzymes are not equivalent and perform pre-defined roles in catalysis.
[]
The active-site histidines of these enzymes are not equivalent and perform pre-defined roles in catalysis.
true
true
true
true
true
6,923
0
DISCUSSION
1
12
[ "B12", "B13", "B13", "B16", "B26", "B27" ]
20,047,964
NA|pmid-1989886|pmid-1989882|pmid-6088516|pmid-16188275|pmid-10194386|pmid-15770420|pmid-12437341|pmid-11839309|pmid-15165852|pmid-15165852|pmid-12470949|pmid-15111055|pmid-15920477
One particular His mounts the nucleophilic attack on the scissile phosphate to make a covalent intermediate (Figure 1B).
[ "12", "13", "13", "16", "26", "27" ]
120
40,121
0
false
One particular His mounts the nucleophilic attack on the scissile phosphate to make a covalent intermediate (Figure 1B).
[]
One particular His mounts the nucleophilic attack on the scissile phosphate to make a covalent intermediate.
true
true
true
true
true
6,923
0
DISCUSSION
1
12
[ "B12", "B13", "B13", "B16", "B26", "B27" ]
20,047,964
NA|pmid-1989886|pmid-1989882|pmid-6088516|pmid-16188275|pmid-10194386|pmid-15770420|pmid-12437341|pmid-11839309|pmid-15165852|pmid-15165852|pmid-12470949|pmid-15111055|pmid-15920477
Not surprisingly, its replacement by site-directed mutagenesis renders the enzyme completely inactive (13,16,26).
[ "12", "13", "13", "16", "26", "27" ]
113
40,122
0
false
Not surprisingly, its replacement by site-directed mutagenesis renders the enzyme completely inactive.
[ "13,16,26" ]
Not surprisingly, its replacement by site-directed mutagenesis renders the enzyme completely inactive.
true
true
true
true
true
6,923
0
DISCUSSION
1
12
[ "B12", "B13", "B13", "B16", "B26", "B27" ]
20,047,964
NA|pmid-1989886|pmid-1989882|pmid-6088516|pmid-16188275|pmid-10194386|pmid-15770420|pmid-12437341|pmid-11839309|pmid-15165852|pmid-15165852|pmid-12470949|pmid-15111055|pmid-15920477
The other His plays a supporting role—it protonates the leaving group during the formation the covalent intermediate and subsequently facilitates the hydrolysis of the phosphohistidine linkage.
[ "12", "13", "13", "16", "26", "27" ]
193
40,123
0
false
The other His plays a supporting role—it protonates the leaving group during the formation the covalent intermediate and subsequently facilitates the hydrolysis of the phosphohistidine linkage.
[]
The other His plays a supporting role—it protonates the leaving group during the formation the covalent intermediate and subsequently facilitates the hydrolysis of the phosphohistidine linkage.
true
true
true
true
true
6,923
0
DISCUSSION
1
27
[ "B12", "B13", "B13", "B16", "B26", "B27" ]
20,047,964
NA|pmid-1989886|pmid-1989882|pmid-6088516|pmid-16188275|pmid-10194386|pmid-15770420|pmid-12437341|pmid-11839309|pmid-15165852|pmid-15165852|pmid-12470949|pmid-15111055|pmid-15920477
Mutations of the latter histidine residue often compromise catalytic activity and result in the accumulation of the covalent intermediate (27).
[ "12", "13", "13", "16", "26", "27" ]
143
40,124
1
false
Mutations of the latter histidine residue often compromise catalytic activity and result in the accumulation of the covalent intermediate.
[ "27" ]
Mutations of the latter histidine residue often compromise catalytic activity and result in the accumulation of the covalent intermediate.
true
true
true
true
true
6,923
1
DISCUSSION
1
10
[ "B10", "B14" ]
20,047,964
pmid-17267608|pmid-10074947|pmid-8732763|pmid-8732763|pmid-11839309|pmid-15165852|pmid-10074947|pmid-16247004|pmid-17028579|pmid-10074947|pmid-15165852|pmid-12470949|pmid-10074947|pmid-16247004
The structurally characterized PLD-family nucleases—Nuc and the restriction endonuclease BfiI (10,14)—are homodimers which contain a single active site structurally similar to that of human Tdp1 and PLD from Streptomyces species.
[ "10", "14" ]
229
40,125
0
false
The structurally characterized PLD-family nucleases—Nuc and the restriction endonuclease BfiI —are homodimers which contain a single active site structurally similar to that of human Tdp1 and PLD from Streptomyces species.
[ "10,14" ]
The structurally characterized PLD-family nucleases—Nuc and the restriction endonuclease BfiI —are homodimers which contain a single active site structurally similar to that of human Tdp1 and PLD from Streptomyces species.
true
true
true
true
true
6,924
1
DISCUSSION
1
10
[ "B10", "B14" ]
20,047,964
pmid-17267608|pmid-10074947|pmid-8732763|pmid-8732763|pmid-11839309|pmid-15165852|pmid-10074947|pmid-16247004|pmid-17028579|pmid-10074947|pmid-15165852|pmid-12470949|pmid-10074947|pmid-16247004
However, in contrast to monomeric PLD enzymes, the active site of BfiI is fully symmetric, as it contains two His residues related by the 2-fold symmetry axis of the dimer, each donated by one enzyme subunit (Figure 1A).
[ "10", "14" ]
220
40,126
0
false
However, in contrast to monomeric PLD enzymes, the active site of BfiI is fully symmetric, as it contains two His residues related by the 2-fold symmetry axis of the dimer, each donated by one enzyme subunit (Figure 1A).
[]
However, in contrast to monomeric PLD enzymes, the active site of BfiI is fully symmetric, as it contains two His residues related by the 2-fold symmetry axis of the dimer, each donated by one enzyme subunit.
true
true
true
true
true
6,924
1
DISCUSSION
1
10
[ "B10", "B14" ]
20,047,964
pmid-17267608|pmid-10074947|pmid-8732763|pmid-8732763|pmid-11839309|pmid-15165852|pmid-10074947|pmid-16247004|pmid-17028579|pmid-10074947|pmid-15165852|pmid-12470949|pmid-10074947|pmid-16247004
This precludes the assignment of the individual roles of each His residue in catalysis.
[ "10", "14" ]
87
40,127
0
false
This precludes the assignment of the individual roles of each His residue in catalysis.
[]
This precludes the assignment of the individual roles of each His residue in catalysis.
true
true
true
true
true
6,924
1
DISCUSSION
1
10
[ "B10", "B14" ]
20,047,964
pmid-17267608|pmid-10074947|pmid-8732763|pmid-8732763|pmid-11839309|pmid-15165852|pmid-10074947|pmid-16247004|pmid-17028579|pmid-10074947|pmid-15165852|pmid-12470949|pmid-10074947|pmid-16247004
To solve this problem, we disrupted the 2-fold symmetry intrinsic to BfiI by constructing heterodimeric forms of the enzyme (Figure 2).
[ "10", "14" ]
135
40,128
0
false
To solve this problem, we disrupted the 2-fold symmetry intrinsic to BfiI by constructing heterodimeric forms of the enzyme (Figure 2).
[]
To solve this problem, we disrupted the 2-fold symmetry intrinsic to BfiI by constructing heterodimeric forms of the enzyme (Figure 2).
true
true
true
true
true
6,924
2
DISCUSSION
1
28
[ "B28", "B5", "B29", "B30", "B5", "B29" ]
20,047,964
NA|pmid-16188275|NA|pmid-1550825|pmid-16188275|NA
WT BfiI forms the covalent intermediate on truncated phosphodiester and 3′-phosphorothiolate substrates with comparable rates (2.1 and 7.7 s−1, respectively: Figure 3E), despite the substantially more acidic leaving group of the 3′-phosphorothiolate substrate [the pKa values of the 3′-SH and 3′-OH groups are ∼11 and ∼1...
[ "28", "5", "29", "30", "5", "29" ]
440
40,129
0
false
WT BfiI forms the covalent intermediate on truncated phosphodiester and 3′-phosphorothiolate substrates with comparable rates (2.1 and 7.7 s−1, respectively: Figure 3E), despite the substantially more acidic leaving group of the 3′-phosphorothiolate substrate, suggesting that protonation of the 3′-leaving group is not ...
[ "the pKa values of the 3′-SH and 3′-OH groups are ∼11 and ∼16, respectively (28)" ]
WT BfiI forms the covalent intermediate on truncated phosphodiester and 3′-phosphorothiolate substrates with comparable rates, despite the substantially more acidic leaving group of the 3′-phosphorothiolate substrate, suggesting that protonation of the 3′-leaving group is not a rate-determining factor for WT BfiI.
true
true
true
true
true
6,925
2
DISCUSSION
1
28
[ "B28", "B5", "B29", "B30", "B5", "B29" ]
20,047,964
NA|pmid-16188275|NA|pmid-1550825|pmid-16188275|NA
The ability of BfiI to cleave the 3′-phosphorothiolate linkage more rapidly than the all-oxygen substrate sharply contrasts with most metal-dependent nucleases (5,29,30).
[ "28", "5", "29", "30", "5", "29" ]
170
40,130
0
false
The ability of BfiI to cleave the 3′-phosphorothiolate linkage more rapidly than the all-oxygen substrate sharply contrasts with most metal-dependent nucleases.
[ "5,29,30" ]
The ability of BfiI to cleave the 3′-phosphorothiolate linkage more rapidly than the all-oxygen substrate sharply contrasts with most metal-dependent nucleases.
true
true
true
true
true
6,925
2
DISCUSSION
1
28
[ "B28", "B5", "B29", "B30", "B5", "B29" ]
20,047,964
NA|pmid-16188275|NA|pmid-1550825|pmid-16188275|NA
These enzymes, unlike the metal independent BfiI, are inhibited by the 3′-S substitution due to its impaired interaction of Mg2+ ions with sulfur; however, some of these enzymes are rescued by the more thiophilic Mn2+ ion (5,29).
[ "28", "5", "29", "30", "5", "29" ]
229
40,131
0
false
These enzymes, unlike the metal independent BfiI, are inhibited by the 3′-S substitution due to its impaired interaction of Mg2+ ions with sulfur; however, some of these enzymes are rescued by the more thiophilic Mn2+ ion.
[ "5,29" ]
These enzymes, unlike the metal independent BfiI, are inhibited by the 3′-S substitution due to its impaired interaction of Mg2+ ions with sulfur; however, some of these enzymes are rescued by the more thiophilic Mn2+ ion.
true
true
true
true
true
6,925
3
DISCUSSION
0
null
null
20,047,964
null
The replacement of one of the active-site histidines with alanine, in the WT/H105A heterodimer, resulted in a dramatic 106-fold decrease in the rate of cleavage of the oxyester bond in the 14/15 oligoduplex (Figure 3E).
null
219
40,132
0
false
null
null
The replacement of one of the active-site histidines with alanine, in the WT/H105A heterodimer, resulted in a dramatic 106-fold decrease in the rate of cleavage of the oxyester bond in the 14/15 oligoduplex (Figure 3E).
true
true
true
true
true
6,926
3
DISCUSSION
0
null
null
20,047,964
null
The residual activity could have been due to a small amount of WT BfiI present in the sample of heterodimer but different preparations of the heterodimer, including the alternative variants WT(6His)/H105A and H105A(6His)/WT, all gave the same low level of activity.
null
265
40,133
0
false
null
null
The residual activity could have been due to a small amount of WT BfiI present in the sample of heterodimer but different preparations of the heterodimer, including the alternative variants WT(6His)/H105A and H105A(6His)/WT, all gave the same low level of activity.
true
true
true
true
true
6,926
3
DISCUSSION
0
null
null
20,047,964
null
Therefore, the observed activity is most likely intrinsic to the WT/H105A heterodimer.
null
86
40,134
0
false
null
null
Therefore, the observed activity is most likely intrinsic to the WT/H105A heterodimer.
true
true
true
true
true
6,926
3
DISCUSSION
0
null
null
20,047,964
null
Thus, the second His105 residue in the active site of BfiI accelerates the formation of the covalent intermediate on the phosphodiester substrate by a factor of at least 106.
null
174
40,135
0
false
null
null
Thus, the second His105 residue in the active site of BfiI accelerates the formation of the covalent intermediate on the phosphodiester substrate by a factor of at least 106.
true
true
true
true
true
6,926
4
DISCUSSION
1
28
[ "B28" ]
20,047,964
pmid-17267608|pmid-10074947|pmid-15165852|pmid-12470949|pmid-12750473|pmid-12750473|NA
Strikingly, the heterodimer cleaved the 3′-phosphorothiolate linkage in the 14/15s duplex 105-fold more rapidly than the phosphodiester group in the original 14/15 substrate (Figure 3E).
[ "28" ]
186
40,136
0
false
Strikingly, the heterodimer cleaved the 3′-phosphorothiolate linkage in the 14/15s duplex 105-fold more rapidly than the phosphodiester group in the original 14/15 substrate (Figure 3E).
[]
Strikingly, the heterodimer cleaved the 3′-phosphorothiolate linkage in the 14/15s duplex 105-fold more rapidly than the phosphodiester group in the original 14/15 substrate (Figure 3E).
true
true
true
true
true
6,927
4
DISCUSSION
1
28
[ "B28" ]
20,047,964
pmid-17267608|pmid-10074947|pmid-15165852|pmid-12470949|pmid-12750473|pmid-12750473|NA
The resultant rate of covalent intermediate formation by the heterodimer (0.19 s−1) is only 40-fold lower than that for the WT enzyme on the same substrate (7.7 s−1, Figure 3E).
[ "28" ]
177
40,137
0
false
The resultant rate of covalent intermediate formation by the heterodimer (0.19 s−1) is only 40-fold lower than that for the WT enzyme on the same substrate (7.7 s−1, Figure 3E).
[]
The resultant rate of covalent intermediate formation by the heterodimer (0.19 s−1) is only 40-fold lower than that for the WT enzyme on the same substrate (7.7 s−1, Figure 3E).
true
true
true
true
true
6,927
4
DISCUSSION
1
28
[ "B28" ]
20,047,964
pmid-17267608|pmid-10074947|pmid-15165852|pmid-12470949|pmid-12750473|pmid-12750473|NA
Furthermore, the rate enhancement over the all-oxygen substrate by a factor of 105 coincides with the pKa difference between the 3′-OH and 3′-SH leaving groups [∼5 units (28)].
[ "28" ]
176
40,138
0
false
Furthermore, the rate enhancement over the all-oxygen substrate by a factor of 105 coincides with the pKa difference between the 3′-OH and 3′-SH leaving groups.
[ "∼5 units (28)" ]
Furthermore, the rate enhancement over the all-oxygen substrate by a factor of 105 coincides with the pKa difference between the 3′-OH and 3′-SH leaving groups.
true
true
true
true
true
6,927
4
DISCUSSION
1
28
[ "B28" ]
20,047,964
pmid-17267608|pmid-10074947|pmid-15165852|pmid-12470949|pmid-12750473|pmid-12750473|NA
These observations argue that one of the two H105 residues in the WT homodimer of BfiI protonates the 3′-leaving group during the first reaction step (Figure 1B): upon its removal, in the WT/H105A heterodimer, the stability of the conjugate base of the 3′-leaving group becomes a major factor governing the reaction rate...
[ "28" ]
321
40,139
0
false
These observations argue that one of the two H105 residues in the WT homodimer of BfiI protonates the 3′-leaving group during the first reaction step (Figure 1B): upon its removal, in the WT/H105A heterodimer, the stability of the conjugate base of the 3′-leaving group becomes a major factor governing the reaction rate...
[]
These observations argue that one of the two H105 residues in the WT homodimer of BfiI protonates the 3′-leaving group during the first reaction step (Figure 1B): upon its removal, in the WT/H105A heterodimer, the stability of the conjugate base of the 3′-leaving group becomes a major factor governing the reaction rate...
true
true
true
true
true
6,927
4
DISCUSSION
1
28
[ "B28" ]
20,047,964
pmid-17267608|pmid-10074947|pmid-15165852|pmid-12470949|pmid-12750473|pmid-12750473|NA
The difference in rate between the heterodimeric and WT enzymes on the 3′-phosphorothiolate substrate implies that even the relatively acidic 3′-thio leaving group must be protonated to achieve the maximum rate of covalent intermediate formation.
[ "28" ]
246
40,140
0
false
The difference in rate between the heterodimeric and WT enzymes on the 3′-phosphorothiolate substrate implies that even the relatively acidic 3′-thio leaving group must be protonated to achieve the maximum rate of covalent intermediate formation.
[]
The difference in rate between the heterodimeric and WT enzymes on the 3′-phosphorothiolate substrate implies that even the relatively acidic 3′-thio leaving group must be protonated to achieve the maximum rate of covalent intermediate formation.
true
true
true
true
true
6,927
5
DISCUSSION
0
null
null
20,047,964
null
The second step in the reaction, the hydrolysis of the covalent enzyme–DNA intermediate (Figure 1B), is an extremely rapid process for WT BfiI (k2 = 170 s−1, Figure 3E).
null
169
40,141
0
false
null
null
The second step in the reaction, the hydrolysis of the covalent enzyme–DNA intermediate (Figure 1B), is an extremely rapid process for WT BfiI (k2 = 170 s−1, Figure 3E).
true
true
true
true
true
6,928
5
DISCUSSION
0
null
null
20,047,964
null
However, the rate is reduced by a factor of 17 000 for the WT/H105A heterodimer (k2 = 0.010 s−1).
null
97
40,142
0
false
null
null
However, the rate is reduced by a factor of 17 000 for the WT/H105A heterodimer (k2 = 0.010 s−1).
true
true
true
true
true
6,928
5
DISCUSSION
0
null
null
20,047,964
null
The dramatic effect of the H105A substitution confirms the direct involvement of the second active-site histidine in the hydrolysis of the covalent phosphohistidine intermediate; presumably, the second histidine activates the water molecule that hydrolyzes the intermediate by removing a proton (Figure 1B).
null
307
40,143
0
false
null
null
The dramatic effect of the H105A substitution confirms the direct involvement of the second active-site histidine in the hydrolysis of the covalent phosphohistidine intermediate; presumably, the second histidine activates the water molecule that hydrolyzes the intermediate by removing a proton (Figure 1B).
true
true
true
true
true
6,928
6
DISCUSSION
1
22
[ "B22", "B24" ]
20,047,964
pmid-9689058|pmid-10207000
The single H105A substitution also reverses the ratio of the reaction rates for the formation (k1) and decay (k2) of the covalent intermediate.
[ "22", "24" ]
143
40,144
0
false
The single H105A substitution also reverses the ratio of the reaction rates for the formation (k1) and decay (k2) of the covalent intermediate.
[]
The single H105A substitution also reverses the ratio of the reaction rates for the formation (k1) and decay of the covalent intermediate.
true
true
true
true
true
6,929
6
DISCUSSION
1
22
[ "B22", "B24" ]
20,047,964
pmid-9689058|pmid-10207000
For WT BfiI on the 14/15s substrate, the ratio of k1/k2 is 0.05, i.e.
[ "22", "24" ]
69
40,145
0
false
For WT BfiI on the 14/15s substrate, the ratio of k1/k2 is 0.05, i.e.
[]
For WT BfiI on the 14/15s substrate, the ratio of k1/k2 is 0.05, i.e.
true
true
true
true
true
6,929
6
DISCUSSION
1
22
[ "B22", "B24" ]
20,047,964
pmid-9689058|pmid-10207000
the covalent intermediate is formed 20 times more slowly than it is hydrolyzed.
[ "22", "24" ]
79
40,146
0
false
the covalent intermediate is formed 20 times more slowly than it is hydrolyzed.
[]
the covalent intermediate is formed 20 times more slowly than it is hydrolyzed.
false
true
true
true
false
6,929
6
DISCUSSION
1
22
[ "B22", "B24" ]
20,047,964
pmid-9689058|pmid-10207000
For the WT(6His)/H105A and H105A/WT-N heterodimers, the ratio of k1/k2 is ≥20, which leads to the accumulation of the covalent intermediate during the reaction (Figures 3C and 4A).
[ "22", "24" ]
180
40,147
0
false
For the WT(6His)/H105A and H105A/WT-N heterodimers, the ratio of k1/k2 is ≥20, which leads to the accumulation of the covalent intermediate during the reaction (Figures 3C and 4A).
[]
For the WT(6His)/H105A and H105A/WT-N heterodimers, the ratio of k1/k2 is ≥20, which leads to the accumulation of the covalent intermediate during the reaction (Figures 3C and 4A).
true
true
true
true
true
6,929
6
DISCUSSION
1
22
[ "B22", "B24" ]
20,047,964
pmid-9689058|pmid-10207000
Biochemical analysis of the low-mobility species postulated to be the covalent intermediate (Supplementary Figure S2) indicated that this was the expected phosphohistidine adduct.
[ "22", "24" ]
179
40,148
0
false
Biochemical analysis of the low-mobility species postulated to be the covalent intermediate (Supplementary Figure S2) indicated that this was the expected phosphohistidine adduct.
[]
Biochemical analysis of the low-mobility species postulated to be the covalent intermediate indicated that this was the expected phosphohistidine adduct.
true
true
true
true
true
6,929
6
DISCUSSION
1
22
[ "B22", "B24" ]
20,047,964
pmid-9689058|pmid-10207000
The covalent intermediate is formed only by the wild type but not the H105A subunit of the heterodimer (Supplementary Figure S2B and D).
[ "22", "24" ]
136
40,149
0
false
The covalent intermediate is formed only by the wild type but not the H105A subunit of the heterodimer (Supplementary Figure S2B and D).
[]
The covalent intermediate is formed only by the wild type but not the H105A subunit of the heterodimer.
true
true
true
true
true
6,929
6
DISCUSSION
1
22
[ "B22", "B24" ]
20,047,964
pmid-9689058|pmid-10207000
Moreover, as expected for a phosphohistidine compound (22,24), the BfiI–DNA adduct is stable at alkaline pH but decomposes in acid (Supplementary Figure S2C).
[ "22", "24" ]
158
40,150
0
false
Moreover, as expected for a phosphohistidine compound, the BfiI–DNA adduct is stable at alkaline pH but decomposes in acid (Supplementary Figure S2C).
[ "22,24" ]
Moreover, as expected for a phosphohistidine compound, the BfiI–DNA adduct is stable at alkaline pH but decomposes in acid.
true
true
true
true
true
6,929
7
DISCUSSION
1
7
[ "B7", "B31", "B32", "B17" ]
20,047,964
pmid-15770420|pmid-8521829|pmid-19052323|pmid-12750473
Nucleases that cut double-stranded DNA often contain two identical subunits related by rotational symmetry, so that the active site from one subunit cleaves the 5′–3′ strand while that from the oppositely-oriented subunit attacks the anti-parallel 3′-5′ strand (7).
[ "7", "31", "32", "17" ]
265
40,151
1
false
Nucleases that cut double-stranded DNA often contain two identical subunits related by rotational symmetry, so that the active site from one subunit cleaves the 5′–3′ strand while that from the oppositely-oriented subunit attacks the anti-parallel 3′-5′ strand.
[ "7" ]
Nucleases that cut double-stranded DNA often contain two identical subunits related by rotational symmetry, so that the active site from one subunit cleaves the 5′–3′ strand while that from the oppositely-oriented subunit attacks the anti-parallel 3′-5′ strand.
true
true
true
true
true
6,930
7
DISCUSSION
1
7
[ "B7", "B31", "B32", "B17" ]
20,047,964
pmid-15770420|pmid-8521829|pmid-19052323|pmid-12750473
However, this strategy cannot be generalized for all nucleases that act on double-stranded DNA.
[ "7", "31", "32", "17" ]
95
40,152
0
false
However, this strategy cannot be generalized for all nucleases that act on double-stranded DNA.
[]
However, this strategy cannot be generalized for all nucleases that act on double-stranded DNA.
true
true
true
true
true
6,930
7
DISCUSSION
1
31
[ "B7", "B31", "B32", "B17" ]
20,047,964
pmid-15770420|pmid-8521829|pmid-19052323|pmid-12750473
A number of enzymes including the homing endonuclease I-TevI (31), the RecBCD complex of E. coli (32) and the BfiI restriction enzyme (17) all utilize single active site to cut both DNA strands, despite their opposite polarities.
[ "7", "31", "32", "17" ]
229
40,153
1
false
A number of enzymes including the homing endonuclease I-TevI, the RecBCD complex of E. coli and the BfiI restriction enzyme all utilize single active site to cut both DNA strands, despite their opposite polarities.
[ "31", "32", "17" ]
A number of enzymes including the homing endonuclease I-TevI, the RecBCD complex of E. coli and the BfiI restriction enzyme all utilize single active site to cut both DNA strands, despite their opposite polarities.
true
true
true
true
true
6,930
8
DISCUSSION
1
33
[ "B33", "B31", "B34", "B35", "B36", "B37", "B38", "B25", "B37" ]
20,047,964
pmid-1762916|pmid-8521829|pmid-12379841|pmid-9724744|pmid-16556912|pmid-9724743|pmid-11491302|pmid-19223323|pmid-9724743
The intron-encoded endonuclease I-TevI is a monomer and contains a single active site but it cuts both DNA strands at the recipient site for intron homing, leaving in both cases products with 3′-hydroxyl and 5′-phosphate termini (33).
[ "33", "31", "34", "35", "36", "37", "38", "25", "37" ]
234
40,154
1
false
The intron-encoded endonuclease I-TevI is a monomer and contains a single active site but it cuts both DNA strands at the recipient site for intron homing, leaving in both cases products with 3′-hydroxyl and 5′-phosphate termini.
[ "33" ]
The intron-encoded endonuclease I-TevI is a monomer and contains a single active site but it cuts both DNA strands at the recipient site for intron homing, leaving in both cases products with 3′-hydroxyl and 5′-phosphate termini.
true
true
true
true
true
6,931
8
DISCUSSION
1
31
[ "B33", "B31", "B34", "B35", "B36", "B37", "B38", "B25", "B37" ]
20,047,964
pmid-1762916|pmid-8521829|pmid-12379841|pmid-9724744|pmid-16556912|pmid-9724743|pmid-11491302|pmid-19223323|pmid-9724743
It is thought that it first cleaves its target phosphodiester bond in the bottom strand and then distorts the DNA to guide into the active site the scissile phosphate from the top strand (31).
[ "33", "31", "34", "35", "36", "37", "38", "25", "37" ]
192
40,155
1
false
It is thought that it first cleaves its target phosphodiester bond in the bottom strand and then distorts the DNA to guide into the active site the scissile phosphate from the top strand.
[ "31" ]
It is thought that it first cleaves its target phosphodiester bond in the bottom strand and then distorts the DNA to guide into the active site the scissile phosphate from the top strand.
true
true
true
true
true
6,931
8
DISCUSSION
1
33
[ "B33", "B31", "B34", "B35", "B36", "B37", "B38", "B25", "B37" ]
20,047,964
pmid-1762916|pmid-8521829|pmid-12379841|pmid-9724744|pmid-16556912|pmid-9724743|pmid-11491302|pmid-19223323|pmid-9724743
However, it is not yet clear how its single active site can accommodate and cut phosphodiester bonds from both the 3′–5′ and the 5′–3′ strands of the DNA, as in both cases it has to displace the leaving group on the 3′ side of the phosphorous at the scissile bond: i.e., in opposite directions on the 3′–5′ compared to t...
[ "33", "31", "34", "35", "36", "37", "38", "25", "37" ]
336
40,156
0
false
However, it is not yet clear how its single active site can accommodate and cut phosphodiester bonds from both the 3′–5′ and the 5′–3′ strands of the DNA, as in both cases it has to displace the leaving group on the 3′ side of the phosphorous at the scissile bond: i.e., in opposite directions on the 3′–5′ compared to t...
[]
However, it is not yet clear how its single active site can accommodate and cut phosphodiester bonds from both the 3′–5′ and the 5′–3′ strands of the DNA, as in both cases it has to displace the leaving group on the 3′ side of the phosphorous at the scissile bond: i.e., in opposite directions on the 3′–5′ compared to t...
true
true
true
true
true
6,931
8
DISCUSSION
1
34
[ "B33", "B31", "B34", "B35", "B36", "B37", "B38", "B25", "B37" ]
20,047,964
pmid-1762916|pmid-8521829|pmid-12379841|pmid-9724744|pmid-16556912|pmid-9724743|pmid-11491302|pmid-19223323|pmid-9724743
Moreover, given the crystal structure of the catalytic domain of I-TevI, alternative reaction schemes, including transient dimerization, cannot be excluded (34).
[ "33", "31", "34", "35", "36", "37", "38", "25", "37" ]
161
40,157
1
false
Moreover, given the crystal structure of the catalytic domain of I-TevI, alternative reaction schemes, including transient dimerization, cannot be excluded.
[ "34" ]
Moreover, given the crystal structure of the catalytic domain of I-TevI, alternative reaction schemes, including transient dimerization, cannot be excluded.
true
true
true
true
true
6,931
8
DISCUSSION
1
33
[ "B33", "B31", "B34", "B35", "B36", "B37", "B38", "B25", "B37" ]
20,047,964
pmid-1762916|pmid-8521829|pmid-12379841|pmid-9724744|pmid-16556912|pmid-9724743|pmid-11491302|pmid-19223323|pmid-9724743
The mode of action of another monomeric endonuclease, FokI, involves transient dimerization (35,36), to give a protein assembly at the recognition site with two catalytic domains juxtaposed in anti-parallel alignment (37,38), which each cut one strand of the DNA.
[ "33", "31", "34", "35", "36", "37", "38", "25", "37" ]
263
40,158
0
false
The mode of action of another monomeric endonuclease, FokI, involves transient dimerization, to give a protein assembly at the recognition site with two catalytic domains juxtaposed in anti-parallel alignment, which each cut one strand of the DNA.
[ "35,36", "37,38" ]
The mode of action of another monomeric endonuclease, FokI, involves transient dimerization, to give a protein assembly at the recognition site with two catalytic domains juxtaposed in anti-parallel alignment, which each cut one strand of the DNA.
true
true
true
true
true
6,931
8
DISCUSSION
1
37
[ "B33", "B31", "B34", "B35", "B36", "B37", "B38", "B25", "B37" ]
20,047,964
pmid-1762916|pmid-8521829|pmid-12379841|pmid-9724744|pmid-16556912|pmid-9724743|pmid-11491302|pmid-19223323|pmid-9724743
In this case, the 1° monomer bound directly to the recognition site cleaves the bottom strand while the 2° monomer recruited to the site by protein–protein interactions cuts the top strand (25), but the symmetry within the dimer of catalytic domains (37) enables one to cut the 3′–5′ strand and the other the 5′–3′ stran...
[ "33", "31", "34", "35", "36", "37", "38", "25", "37" ]
322
40,159
1
false
In this case, the 1° monomer bound directly to the recognition site cleaves the bottom strand while the 2° monomer recruited to the site by protein–protein interactions cuts the top strand, but the symmetry within the dimer of catalytic domains enables one to cut the 3′–5′ strand and the other the 5′–3′ strand.
[ "25", "37" ]
In this case, the 1° monomer bound directly to the recognition site cleaves the bottom strand while the 2° monomer recruited to the site by protein–protein interactions cuts the top strand, but the symmetry within the dimer of catalytic domains enables one to cut the 3′–5′ strand and the other the 5′–3′ strand.
true
true
true
true
true
6,931
9
DISCUSSION
1
32
[ "B32", "B39", "B40" ]
20,047,964
pmid-19052323|pmid-10617645|pmid-15538360
The E. coli RecBCD enzyme acts in the repair of double-stranded DNA breaks as a trimeric protein with multiple catalytic activities that include two helicase functions, both 3′→5′ and 5′→3′ in the B and D subunits respectively and a single endonuclease function, located in B from where it degrades both strands (32).
[ "32", "39", "40" ]
317
40,160
1
false
The E. coli RecBCD enzyme acts in the repair of double-stranded DNA breaks as a trimeric protein with multiple catalytic activities that include two helicase functions, both 3′→5′ and 5′→3′ in the B and D subunits respectively and a single endonuclease function, located in B from where it degrades both strands.
[ "32" ]
The E. coli RecBCD enzyme acts in the repair of double-stranded DNA breaks as a trimeric protein with multiple catalytic activities that include two helicase functions, both 3′→5′ and 5′→3′ in the B and D subunits respectively and a single endonuclease function, located in B from where it degrades both strands.
true
true
true
true
true
6,932
9
DISCUSSION
1
39
[ "B32", "B39", "B40" ]
20,047,964
pmid-19052323|pmid-10617645|pmid-15538360
To account for how the nuclease cleaves both of the newly unwound strands despite their opposite polarities, it was suggested that the nascent 3′-terminus generated by RecB progresses directly into the nuclease centre, which is also in B, while the nascent 5′-terminus generated by RecD forms a loop before entering the ...
[ "32", "39", "40" ]
390
40,161
1
false
To account for how the nuclease cleaves both of the newly unwound strands despite their opposite polarities, it was suggested that the nascent 3′-terminus generated by RecB progresses directly into the nuclease centre, which is also in B, while the nascent 5′-terminus generated by RecD forms a loop before entering the ...
[ "39" ]
To account for how the nuclease cleaves both of the newly unwound strands despite their opposite polarities, it was suggested that the nascent 3′-terminus generated by RecB progresses directly into the nuclease centre, which is also in B, while the nascent 5′-terminus generated by RecD forms a loop before entering the ...
true
true
true
true
true
6,932
9
DISCUSSION
1
40
[ "B32", "B39", "B40" ]
20,047,964
pmid-19052323|pmid-10617645|pmid-15538360
However, this model has yet to be confirmed experimentally, though it can readily be reconciled to the crystal structure of RecBCD (40).
[ "32", "39", "40" ]
136
40,162
1
false
However, this model has yet to be confirmed experimentally, though it can readily be reconciled to the crystal structure of RecBCD.
[ "40" ]
However, this model has yet to be confirmed experimentally, though it can readily be reconciled to the crystal structure of RecBCD.
true
true
true
true
true
6,932
10
DISCUSSION
1
17
[ "B17", "B17" ]
20,047,964
pmid-12750473|pmid-12750473
The BfiI restriction enzyme employs yet another strategy.
[ "17", "17" ]
57
40,163
0
false
The BfiI restriction enzyme employs yet another strategy.
[]
The BfiI restriction enzyme employs yet another strategy.
true
true
true
true
true
6,933
10
DISCUSSION
1
17
[ "B17", "B17" ]
20,047,964
pmid-12750473|pmid-12750473
It had been shown previously that it uses a single active site to cut both DNA strands downstream of its recognition site in sequential steps, in a fixed order; first the bottom and only then the top strand (17).
[ "17", "17" ]
212
40,164
1
false
It had been shown previously that it uses a single active site to cut both DNA strands downstream of its recognition site in sequential steps, in a fixed order; first the bottom and only then the top strand.
[ "17" ]
It had been shown previously that it uses a single active site to cut both DNA strands downstream of its recognition site in sequential steps, in a fixed order; first the bottom and only then the top strand.
true
true
true
true
true
6,933
10
DISCUSSION
1
17
[ "B17", "B17" ]
20,047,964
pmid-12750473|pmid-12750473
The BfiI endonuclease contains two symmetrically-positioned His residues at the active site, so it was proposed that BfiI cuts one strand by using the histidine from one subunit as the nucleophile and that from the other subunit as the proton donor/acceptor, while these roles are reversed for cutting the complementary ...
[ "17", "17" ]
353
40,165
1
false
The BfiI endonuclease contains two symmetrically-positioned His residues at the active site, so it was proposed that BfiI cuts one strand by using the histidine from one subunit as the nucleophile and that from the other subunit as the proton donor/acceptor, while these roles are reversed for cutting the complementary ...
[ "17" ]
The BfiI endonuclease contains two symmetrically-positioned His residues at the active site, so it was proposed that BfiI cuts one strand by using the histidine from one subunit as the nucleophile and that from the other subunit as the proton donor/acceptor, while these roles are reversed for cutting the complementary ...
true
true
true
true
true
6,933
11
DISCUSSION
0
null
null
20,047,964
null
In this article, this hypothesis was tested experimentally by using truncated heterodimers of BfiI that lack the DNA-binding domain from one subunit: from either the subunit carrying the inactivating H105A mutation, WT/H105A-N; or from the WT subunit, H105A/WT-N.
null
263
40,166
0
false
null
null
In this article, this hypothesis was tested experimentally by using truncated heterodimers of BfiI that lack the DNA-binding domain from one subunit: from either the subunit carrying the inactivating H105A mutation, WT/H105A-N; or from the WT subunit, H105A/WT-N.
true
true
true
true
true
6,934
11
DISCUSSION
0
null
null
20,047,964
null
Contrary to the full length heterodimers bearing both DNA recognition domains (Figure 3D), each truncated heterodimer has to bind DNA in a specified orientation: either the productive orientation in which the His105 residue from the WT subunit is positioned for the in-line attack on the scissile phosphate; or the non-p...
null
451
40,167
0
false
null
null
Contrary to the full length heterodimers bearing both DNA recognition domains (Figure 3D), each truncated heterodimer has to bind DNA in a specified orientation: either the productive orientation in which the His105 residue from the WT subunit is positioned for the in-line attack on the scissile phosphate; or the non-p...
true
true
true
true
true
6,934
11
DISCUSSION
0
null
null
20,047,964
null
Hence, if the WT/H105-N heterodimer shows catalytic activity, the covalent intermediate is formed by the histidine from the full-length enzyme subunit bound to the target site on DNA, the 1° subunit.
null
199
40,168
0
false
null
null
Hence, if the WT/H105-N heterodimer shows catalytic activity, the covalent intermediate is formed by the histidine from the full-length enzyme subunit bound to the target site on DNA, the 1° subunit.
true
true
true
true
true
6,934
11
DISCUSSION
0
null
null
20,047,964
null
Alternatively, if the H105A/WT-N variant displays activity, the histidine nucleophile comes from the truncated subunit that is not bound to the recognition sequence, the 2° subunit.
null
181
40,169
0
false
null
null
Alternatively, if the H105A/WT-N variant displays activity, the histidine nucleophile comes from the truncated subunit that is not bound to the recognition sequence, the 2° subunit.
true
true
true
true
true
6,934
11
DISCUSSION
0
null
null
20,047,964
null
Thus, by analyzing the activities of the truncated heterodimers, we were able to identify directly which histidine residue forms the covalent intermediate during the cleavage of the bottom (3′–5′) and the top (5′–3′) DNA strands.
null
229
40,170
0
false
null
null
Thus, by analyzing the activities of the truncated heterodimers, we were able to identify directly which histidine residue forms the covalent intermediate during the cleavage of the bottom (3′–5′) and the top (5′–3′) DNA strands.
true
true
true
true
true
6,934
12
DISCUSSION
0
null
null
20,047,964
null
Contrary to the suggestion that H105 from one particular subunit of BfiI attacks the scissile bond in the bottom (3′–5′) DNA strand while the symmetry-related H105 from the opposite subunit takes this role for cutting the top (5′–3′) strand, it was found here the His from the 2° subunit not bound to the recognition sit...
null
407
40,171
0
false
null
null
Contrary to the suggestion that H105 from one particular subunit of BfiI attacks the scissile bond in the bottom (3′–5′) DNA strand while the symmetry-related H105 from the opposite subunit takes this role for cutting the top (5′–3′) strand, it was found here the His from the 2° subunit not bound to the recognition sit...
true
true
true
true
true
6,935
12
DISCUSSION
0
null
null
20,047,964
null
The equivalent histidine from the DNA-bound 1° subunit presumably acts as the proton donor/acceptor for the reactions on both strands.
null
134
40,172
0
false
null
null
The equivalent histidine from the DNA-bound 1° subunit presumably acts as the proton donor/acceptor for the reactions on both strands.
true
true
true
true
true
6,935
12
DISCUSSION
0
null
null
20,047,964
null
To match the anti-parallel polarity of the two DNA strands, the catalytic center of BfiI therefore must rotate by 180° between the two hydrolysis reactions (Figure 4C).
null
168
40,173
0
false
null
null
To match the anti-parallel polarity of the two DNA strands, the catalytic center of BfiI therefore must rotate by 180° between the two hydrolysis reactions (Figure 4C).
true
true
true
true
true
6,935
12
DISCUSSION
0
null
null
20,047,964
null
Thus, we demonstrate here a novel mechanism for the scission of double-stranded DNA as it requires a single active site to not only switch between strands but also to switch its orientation on the DNA.
null
201
40,174
0
false
null
null
Thus, we demonstrate here a novel mechanism for the scission of double-stranded DNA as it requires a single active site to not only switch between strands but also to switch its orientation on the DNA.
true
true
true
true
true
6,935
13
DISCUSSION
1
18
[ "B18" ]
20,047,964
pmid-12589753
The above reactions all contained BfiI in excess over the DNA, to favor binding of a single DNA molecule to each enzyme dimer.
[ "18" ]
126
40,175
0
false
The above reactions all contained BfiI in excess over the DNA, to favor binding of a single DNA molecule to each enzyme dimer.
[]
The above reactions all contained BfiI in excess over the DNA, to favor binding of a single DNA molecule to each enzyme dimer.
true
true
true
true
true
6,936
13
DISCUSSION
1
18
[ "B18" ]
20,047,964
pmid-12589753
However, BfiI is optimally active when bound to two copies of its recognition sequence (18).
[ "18" ]
92
40,176
1
false
However, BfiI is optimally active when bound to two copies of its recognition sequence.
[ "18" ]
However, BfiI is optimally active when bound to two copies of its recognition sequence.
true
true
true
true
true
6,936
13
DISCUSSION
1
18
[ "B18" ]
20,047,964
pmid-12589753
To cut four phosphodiester bonds across two target sites, the single active site in the BfiI dimer must relocate between the scissile phosphates in the two sites, cleaving one phosphodiester bond at a time.
[ "18" ]
206
40,177
0
false
To cut four phosphodiester bonds across two target sites, the single active site in the BfiI dimer must relocate between the scissile phosphates in the two sites, cleaving one phosphodiester bond at a time.
[]
To cut four phosphodiester bonds across two target sites, the single active site in the BfiI dimer must relocate between the scissile phosphates in the two sites, cleaving one phosphodiester bond at a time.
true
true
true
true
true
6,936
13
DISCUSSION
1
18
[ "B18" ]
20,047,964
pmid-12589753
In the synaptic complex of the BfiI dimer with two recognition sites (Figure 4D), one subunit (B) is attached via its DNA-binding domain to recognition site X while the other subunit (A) is attached to site Y.
[ "18" ]
209
40,178
0
false
In the synaptic complex of the BfiI dimer with two recognition sites (Figure 4D), one subunit (B) is attached via its DNA-binding domain to recognition site X while the other subunit (A) is attached to site Y.
[]
In the synaptic complex of the BfiI dimer with two recognition sites (Figure 4D), one subunit (B) is attached via its DNA-binding domain to recognition site X while the other subunit (A) is attached to site Y.
true
true
true
true
true
6,936
13
DISCUSSION
1
18
[ "B18" ]
20,047,964
pmid-12589753
This leaves subunit A as the 2° subunit with respect to recognition site X so H105 from A presumably forms the covalent intermediate during the sequential cutting of both strands at site X, while H105 from subunit B fulfils the proton donor/acceptor roles in both strand-scission events.
[ "18" ]
287
40,179
0
false
This leaves subunit A as the 2° subunit with respect to recognition site X so H105 from A presumably forms the covalent intermediate during the sequential cutting of both strands at site X, while H105 from subunit B fulfils the proton donor/acceptor roles in both strand-scission events.
[]
This leaves subunit A as the 2° subunit with respect to recognition site X so H105 from A presumably forms the covalent intermediate during the sequential cutting of both strands at site X, while H105 from subunit B fulfils the proton donor/acceptor roles in both strand-scission events.
true
true
true
true
true
6,936
13
DISCUSSION
1
18
[ "B18" ]
20,047,964
pmid-12589753
Conversely, subunit B is the 2° subunit for site Y so, for cutting this second site, the H105 residues from the B and the A subunits should fulfill the same roles as those played by, respectively, the A and the B subunits when cutting site X.
[ "18" ]
242
40,180
0
false
Conversely, subunit B is the 2° subunit for site Y so, for cutting this second site, the H105 residues from the B and the A subunits should fulfill the same roles as those played by, respectively, the A and the B subunits when cutting site X.
[]
Conversely, subunit B is the 2° subunit for site Y so, for cutting this second site, the H105 residues from the B and the A subunits should fulfill the same roles as those played by, respectively, the A and the B subunits when cutting site X.
true
true
true
true
true
6,936
13
DISCUSSION
1
18
[ "B18" ]
20,047,964
pmid-12589753
Hence, the two His residues may switch roles while cleaving two specific sites bound to an enzyme dimer (Figure 4D), though it will always be the histidine from one particular subunit that attacks both bottom and top strands at each DNA site (Figure 4C).
[ "18" ]
254
40,181
0
false
Hence, the two His residues may switch roles while cleaving two specific sites bound to an enzyme dimer (Figure 4D), though it will always be the histidine from one particular subunit that attacks both bottom and top strands at each DNA site (Figure 4C).
[]
Hence, the two His residues may switch roles while cleaving two specific sites bound to an enzyme dimer (Figure 4D), though it will always be the histidine from one particular subunit that attacks both bottom and top strands at each DNA site (Figure 4C).
true
true
true
true
true
6,936
0
DISCUSSION
0
null
null
18,614,536
null
The present data have demonstrated that SOCS3 protects photoreceptor cells from severe down-regulation of rhodopsin protein and prolonged visual dysfunction during retinal inflammation.
null
187
40,182
0
false
null
null
The present data have demonstrated that SOCS3 protects photoreceptor cells from severe down-regulation of rhodopsin protein and prolonged visual dysfunction during retinal inflammation.
true
true
true
true
true
6,937
0
DISCUSSION
0
null
null
18,614,536
null
Elevated STAT3 activation decreased rhodopsin at the post-transcriptional level through degradation by the UPS.
null
112
40,183
0
false
null
null
Elevated STAT3 activation decreased rhodopsin at the post-transcriptional level through degradation by the UPS.
true
true
true
true
true
6,937
0
DISCUSSION
0
null
null
18,614,536
null
SOCS3 effectively inhibited STAT3 activation and blocked further photoreceptor cell dysfunction.
null
97
40,184
0
false
null
null
SOCS3 effectively inhibited STAT3 activation and blocked further photoreceptor cell dysfunction.
true
true
true
true
true
6,937
1
DISCUSSION
0
null
null
18,614,536
null
SOCS3 Minimizes Visual Dysfunction during Retinal Inflammation—We demonstrated that STAT3 activation, among several intracellular signaling pathways induced during retinal inflammation, was critical for visual function and that SOCS3 was a key endogenous molecule for neuroprotection.
null
288
40,185
0
false
null
null
SOCS3 Minimizes Visual Dysfunction during Retinal Inflammation—We demonstrated that STAT3 activation, among several intracellular signaling pathways induced during retinal inflammation, was critical for visual function and that SOCS3 was a key endogenous molecule for neuroprotection.
true
true
true
true
true
6,938
1
DISCUSSION
0
null
null
18,614,536
null
Although rhodopsin expression was also significantly down-regulated in wild-type mice when STAT3 activation reached a certain level, this change was more rapid and profound in α-Cre SOCS3flox/flox mice (Fig.
null
211
40,186
0
false
null
null
Although rhodopsin expression was also significantly down-regulated in wild-type mice when STAT3 activation reached a certain level, this change was more rapid and profound in α-Cre SOCS3flox/flox mice (Fig.
true
true
true
true
true
6,938
1
DISCUSSION
0
null
null
18,614,536
null
2, A and D), indicating that SOCS3 was required to minimize and recover from the retinal dysfunction.
null
103
40,187
0
false
null
null
2, A and D), indicating that SOCS3 was required to minimize and recover from the retinal dysfunction.
false
false
true
true
false
6,938
1
DISCUSSION
0
null
null
18,614,536
null
This also suggested that SOCS3 deficiency compromised the ability of their photoreceptor cells to withstand inflammatory stress.
null
130
40,188
0
false
null
null
This also suggested that SOCS3 deficiency compromised the ability of their photoreceptor cells to withstand inflammatory stress.
true
true
true
true
true
6,938
1
DISCUSSION
0
null
null
18,614,536
null
SOCS3 may have an important role in balancing STAT3 activation during fluctuations of the microenvironment in daily life, and by so doing, SOCS3 may help avoid the development of severe inflammation.
null
201
40,189
0
false
null
null
SOCS3 may have an important role in balancing STAT3 activation during fluctuations of the microenvironment in daily life, and by so doing, SOCS3 may help avoid the development of severe inflammation.
true
true
true
true
true
6,938
2
DISCUSSION
1
10
[ "ref10", "ref25", "ref37", "ref38", "ref2", "ref39" ]
18,614,536
pmid-17198696|pmid-12754507|pmid-16630890|pmid-16966486|pmid-11748261|pmid-16007096
Rhodopsin expression was better preserved, but still reduced, in the wild-type mice during the course of inflammation.
[ "10", "25", "37", "38", "2", "39" ]
119
40,190
0
false
Rhodopsin expression was better preserved, but still reduced, in the wild-type mice during the course of inflammation.
[]
Rhodopsin expression was better preserved, but still reduced, in the wild-type mice during the course of inflammation.
true
true
true
true
true
6,939
2
DISCUSSION
1
10
[ "ref10", "ref25", "ref37", "ref38", "ref2", "ref39" ]
18,614,536
pmid-17198696|pmid-12754507|pmid-16630890|pmid-16966486|pmid-11748261|pmid-16007096
This is more likely because the level of SOCS3 expression is not sufficient to significantly suppress the active phosphorylation of STAT3 by JAK, which had been induced by the strong inflammatory stimuli, even though the SOCS3 expression is induced.
[ "10", "25", "37", "38", "2", "39" ]
252
40,191
0
false
This is more likely because the level of SOCS3 expression is not sufficient to significantly suppress the active phosphorylation of STAT3 by JAK, which had been induced by the strong inflammatory stimuli, even though the SOCS3 expression is induced.
[]
This is more likely because the level of SOCS3 expression is not sufficient to significantly suppress the active phosphorylation of STAT3 by JAK, which had been induced by the strong inflammatory stimuli, even though the SOCS3 expression is induced.
true
true
true
true
true
6,939
2
DISCUSSION
1
10
[ "ref10", "ref25", "ref37", "ref38", "ref2", "ref39" ]
18,614,536
pmid-17198696|pmid-12754507|pmid-16630890|pmid-16966486|pmid-11748261|pmid-16007096
Although exposure to IL-6 alone reduced rhodopsin in adult retinal explants, several kinds of inflammatory cytokines that activate STAT3 more intensively in vivo should be induced simultaneously during inflammation.
[ "10", "25", "37", "38", "2", "39" ]
218
40,192
0
false
Although exposure to IL-6 alone reduced rhodopsin in adult retinal explants, several kinds of inflammatory cytokines that activate STAT3 more intensively in vivo should be induced simultaneously during inflammation.
[]
Although exposure to IL-6 alone reduced rhodopsin in adult retinal explants, several kinds of inflammatory cytokines that activate STAT3 more intensively in vivo should be induced simultaneously during inflammation.
true
true
true
true
true
6,939
2
DISCUSSION
1
10
[ "ref10", "ref25", "ref37", "ref38", "ref2", "ref39" ]
18,614,536
pmid-17198696|pmid-12754507|pmid-16630890|pmid-16966486|pmid-11748261|pmid-16007096
The level of SOCS3 is itself regulated by several kinds of post-transcriptional inhibitory mechanisms (10, 25, 37), which may also cause the insufficiency under high levels of STAT3 activation.
[ "10", "25", "37", "38", "2", "39" ]
198
40,193
0
false
The level of SOCS3 is itself regulated by several kinds of post-transcriptional inhibitory mechanisms, which may also cause the insufficiency under high levels of STAT3 activation.
[ "10,\n 25,\n 37" ]
The level of SOCS3 is itself regulated by several kinds of post-transcriptional inhibitory mechanisms, which may also cause the insufficiency under high levels of STAT3 activation.
true
true
true
true
true
6,939
2
DISCUSSION
1
10
[ "ref10", "ref25", "ref37", "ref38", "ref2", "ref39" ]
18,614,536
pmid-17198696|pmid-12754507|pmid-16630890|pmid-16966486|pmid-11748261|pmid-16007096
The inadequate SOCS3 activity may cause visual dysfunction also in other situations.
[ "10", "25", "37", "38", "2", "39" ]
85
40,194
0
false
The inadequate SOCS3 activity may cause visual dysfunction also in other situations.
[]
The inadequate SOCS3 activity may cause visual dysfunction also in other situations.
true
true
true
true
true
6,939
2
DISCUSSION
1
10
[ "ref10", "ref25", "ref37", "ref38", "ref2", "ref39" ]
18,614,536
pmid-17198696|pmid-12754507|pmid-16630890|pmid-16966486|pmid-11748261|pmid-16007096
STAT3 activation induced by CNTF administration for therapy in retinitis pigmentosa may easily exceed the activity of endogenous SOCS3 and induce excessive STAT3 activation.
[ "10", "25", "37", "38", "2", "39" ]
176
40,195
0
false
STAT3 activation induced by CNTF administration for therapy in retinitis pigmentosa may easily exceed the activity of endogenous SOCS3 and induce excessive STAT3 activation.
[]
STAT3 activation induced by CNTF administration for therapy in retinitis pigmentosa may easily exceed the activity of endogenous SOCS3 and induce excessive STAT3 activation.
true
true
true
true
true
6,939
2
DISCUSSION
1
38
[ "ref10", "ref25", "ref37", "ref38", "ref2", "ref39" ]
18,614,536
pmid-17198696|pmid-12754507|pmid-16630890|pmid-16966486|pmid-11748261|pmid-16007096
Other examples are retinal degeneration and light damage (38), which also up-regulates CNTF/gp130-STAT3 signaling in the retina.
[ "10", "25", "37", "38", "2", "39" ]
130
40,196
1
false
Other examples are retinal degeneration and light damage, which also up-regulates CNTF/gp130-STAT3 signaling in the retina.
[ "38" ]
Other examples are retinal degeneration and light damage, which also up-regulates CNTF/gp130-STAT3 signaling in the retina.
true
true
true
true
true
6,939
2
DISCUSSION
1
10
[ "ref10", "ref25", "ref37", "ref38", "ref2", "ref39" ]
18,614,536
pmid-17198696|pmid-12754507|pmid-16630890|pmid-16966486|pmid-11748261|pmid-16007096
In these retinas, rhodopsin degradation may be accelerated, causing increased deterioration of retinal function when STAT3 activation surpasses endogenous SOCS3 activity.
[ "10", "25", "37", "38", "2", "39" ]
172
40,197
0
false
In these retinas, rhodopsin degradation may be accelerated, causing increased deterioration of retinal function when STAT3 activation surpasses endogenous SOCS3 activity.
[]
In these retinas, rhodopsin degradation may be accelerated, causing increased deterioration of retinal function when STAT3 activation surpasses endogenous SOCS3 activity.
true
true
true
true
true
6,939
2
DISCUSSION
1
10
[ "ref10", "ref25", "ref37", "ref38", "ref2", "ref39" ]
18,614,536
pmid-17198696|pmid-12754507|pmid-16630890|pmid-16966486|pmid-11748261|pmid-16007096
As several kinds of cytokine signals that activate STAT3 are up-regulated during inflammation, it would be a great advantage for SOCS3 to simultaneously shut down several of the pathologic signaling pathways by directly inhibiting JAK, commonly found downstream of the gp130 signals, as compared with the strategy d...
[ "10", "25", "37", "38", "2", "39" ]
352
40,198
0
false
As several kinds of cytokine signals that activate STAT3 are up-regulated during inflammation, it would be a great advantage for SOCS3 to simultaneously shut down several of the pathologic signaling pathways by directly inhibiting JAK, commonly found downstream of the gp130 signals, as compared with the strategy design...
[]
As several kinds of cytokine signals that activate STAT3 are up-regulated during inflammation, it would be a great advantage for SOCS3 to simultaneously shut down several of the pathologic signaling pathways by directly inhibiting JAK, commonly found downstream of the gp130 signals, as compared with the strategy design...
true
true
true
true
true
6,939
2
DISCUSSION
1
10
[ "ref10", "ref25", "ref37", "ref38", "ref2", "ref39" ]
18,614,536
pmid-17198696|pmid-12754507|pmid-16630890|pmid-16966486|pmid-11748261|pmid-16007096
Further study may support the development of the SOCS3 protein as a therapeutic target (2, 39).
[ "10", "25", "37", "38", "2", "39" ]
98
40,199
0
false
Further study may support the development of the SOCS3 protein as a therapeutic target.
[ "2,\n 39" ]
Further study may support the development of the SOCS3 protein as a therapeutic target.
true
true
true
true
true
6,939
3
DISCUSSION
1
40
[ "ref40", "ref41" ]
18,614,536
pmid-8662797|pmid-12091393
Proposed Mechanism for SOCS3 to Inhibit the UPS-dependent Degradation of Rhodopsin—The rapid decrease in rhodopsin protein at least in part involved UPS-mediated degradation.
[ "40", "41" ]
176
40,200
0
false
Proposed Mechanism for SOCS3 to Inhibit the UPS-dependent Degradation of Rhodopsin—The rapid decrease in rhodopsin protein at least in part involved UPS-mediated degradation.
[]
Proposed Mechanism for SOCS3 to Inhibit the UPS-dependent Degradation of Rhodopsin—The rapid decrease in rhodopsin protein at least in part involved UPS-mediated degradation.
true
true
true
true
true
6,940
3
DISCUSSION
1
40
[ "ref40", "ref41" ]
18,614,536
pmid-8662797|pmid-12091393
Although rhodopsin is not metabolized through the UPS under normal condition (40), it can be degraded rapidly through the UPS under pathologic conditions (41).
[ "40", "41" ]
163
40,201
1
false
Although rhodopsin is not metabolized through the UPS under normal condition, it can be degraded rapidly through the UPS under pathologic conditions.
[ "40", "41" ]
Although rhodopsin is not metabolized through the UPS under normal condition, it can be degraded rapidly through the UPS under pathologic conditions.
true
true
true
true
true
6,940
4
DISCUSSION
1
41
[ "ref41", "ref42", "ref43", "ref43" ]
18,614,536
pmid-12091393|pmid-12082151|pmid-10476808|pmid-10476808
A mutant rhodopsin, P23H, which causes an autosomal dominant form of retinitis pigmentosa, folds abnormally and accumulates in aggresomes instead of proceeding to the normal transport to the cell membrane (41, 42).
[ "41", "42", "43", "43" ]
218
40,202
0
false
A mutant rhodopsin, P23H, which causes an autosomal dominant form of retinitis pigmentosa, folds abnormally and accumulates in aggresomes instead of proceeding to the normal transport to the cell membrane.
[ "41,\n 42" ]
A mutant rhodopsin, P23H, which causes an autosomal dominant form of retinitis pigmentosa, folds abnormally and accumulates in aggresomes instead of proceeding to the normal transport to the cell membrane.
true
true
true
true
true
6,941
4
DISCUSSION
1
41
[ "ref41", "ref42", "ref43", "ref43" ]
18,614,536
pmid-12091393|pmid-12082151|pmid-10476808|pmid-10476808
However, the wild-type rhodopsin protein was also ubiquitinated (Figs.
[ "41", "42", "43", "43" ]
71
40,203
0
false
However, the wild-type rhodopsin protein was also ubiquitinated (Figs.
[]
However, the wild-type rhodopsin protein was also ubiquitinated (Figs.
true
true
true
true
true
6,941
4
DISCUSSION
1
41
[ "ref41", "ref42", "ref43", "ref43" ]
18,614,536
pmid-12091393|pmid-12082151|pmid-10476808|pmid-10476808
4C and 7), suggesting that a normal rhodopsin protein may undergo abnormal post-translational modification and misfolding, which leads to degradation by the UPS in response to stress stimuli.
[ "41", "42", "43", "43" ]
195
40,204
0
false
4C and 7), suggesting that a normal rhodopsin protein may undergo abnormal post-translational modification and misfolding, which leads to degradation by the UPS in response to stress stimuli.
[]
4C and 7), suggesting that a normal rhodopsin protein may undergo abnormal post-translational modification and misfolding, which leads to degradation by the UPS in response to stress stimuli.
false
false
true
true
false
6,941
4
DISCUSSION
1
43
[ "ref41", "ref42", "ref43", "ref43" ]
18,614,536
pmid-12091393|pmid-12082151|pmid-10476808|pmid-10476808
Ubiquitin protein is already present in the rod outer segment under control conditions (43), and thus it may lead rhodopsin protein degraded so rapidly.
[ "41", "42", "43", "43" ]
154
40,205
1
false
Ubiquitin protein is already present in the rod outer segment under control conditions, and thus it may lead rhodopsin protein degraded so rapidly.
[ "43" ]
Ubiquitin protein is already present in the rod outer segment under control conditions, and thus it may lead rhodopsin protein degraded so rapidly.
true
true
true
true
true
6,941
4
DISCUSSION
1
43
[ "ref41", "ref42", "ref43", "ref43" ]
18,614,536
pmid-12091393|pmid-12082151|pmid-10476808|pmid-10476808
The authors (43) also showed that rhodopsin and ubiquitin proteins are both observed in the same vesicles especially after light exposure, supporting the idea that genetically normal rhodopsin may be degraded through the UPS under pathological conditions.
[ "41", "42", "43", "43" ]
259
40,206
1
false
The authors also showed that rhodopsin and ubiquitin proteins are both observed in the same vesicles especially after light exposure, supporting the idea that genetically normal rhodopsin may be degraded through the UPS under pathological conditions.
[ "43" ]
The authors also showed that rhodopsin and ubiquitin proteins are both observed in the same vesicles especially after light exposure, supporting the idea that genetically normal rhodopsin may be degraded through the UPS under pathological conditions.
true
true
true
true
true
6,941
5
DISCUSSION
1
40
[ "ref40", "ref33", "ref34" ]
18,614,536
pmid-8662797|NA|pmid-17018293
Activated STAT3 regulated multi-ubiquitination (Fig.
[ "40", "33", "34" ]
53
40,207
0
false
Activated STAT3 regulated multi-ubiquitination (Fig.
[]
Activated STAT3 regulated multi-ubiquitination (Fig.
true
true
true
true
true
6,942
5
DISCUSSION
1
40
[ "ref40", "ref33", "ref34" ]
18,614,536
pmid-8662797|NA|pmid-17018293
Thus, we deduced Ubr1 as a selective E3 ubiquitin ligase for rhodopsin degradation as follows.
[ "40", "33", "34" ]
96
40,208
0
false
Thus, we deduced Ubr1 as a selective E3 ubiquitin ligase for rhodopsin degradation as follows.
[]
Thus, we deduced Ubr1 as a selective E3 ubiquitin ligase for rhodopsin degradation as follows.
true
true
true
true
true
6,942
5
DISCUSSION
1
40
[ "ref40", "ref33", "ref34" ]
18,614,536
pmid-8662797|NA|pmid-17018293
An ubiquitin-conjugating enzmye, E214k, required for “N-end rule” proteolysis, is abundant in the fraction of rod outer segments as well as rhodopsin (40).
[ "40", "33", "34" ]
158
40,209
1
false
An ubiquitin-conjugating enzmye, E214k, required for “N-end rule” proteolysis, is abundant in the fraction of rod outer segments as well as rhodopsin.
[ "40" ]
An ubiquitin-conjugating enzmye, E214k, required for “N-end rule” proteolysis, is abundant in the fraction of rod outer segments as well as rhodopsin.
true
true
true
true
true
6,942
5
DISCUSSION
1
33
[ "ref40", "ref33", "ref34" ]
18,614,536
pmid-8662797|NA|pmid-17018293
E214k, which is indispensable for the catabolism of skeletal muscle during fasting, interacts with a selective E3 ubiquitin ligase, Ubr1 (33).
[ "40", "33", "34" ]
145
40,210
1
false
E214k, which is indispensable for the catabolism of skeletal muscle during fasting, interacts with a selective E3 ubiquitin ligase, Ubr1.
[ "33" ]
E214k, which is indispensable for the catabolism of skeletal muscle during fasting, interacts with a selective E3 ubiquitin ligase, Ubr1.
true
true
true
true
true
6,942
5
DISCUSSION
1
40
[ "ref40", "ref33", "ref34" ]
18,614,536
pmid-8662797|NA|pmid-17018293
Because an E2 and E3 enzymes act with a particular combination to degrade specific target proteins, E214k and Ubr1 could be involved in the selective degradation of rhodopsin protein observed in this study.
[ "40", "33", "34" ]
209
40,211
0
false
Because an E2 and E3 enzymes act with a particular combination to degrade specific target proteins, E214k and Ubr1 could be involved in the selective degradation of rhodopsin protein observed in this study.
[]
Because an E2 and E3 enzymes act with a particular combination to degrade specific target proteins, E214k and Ubr1 could be involved in the selective degradation of rhodopsin protein observed in this study.
true
true
true
true
true
6,942
5
DISCUSSION
1
34
[ "ref40", "ref33", "ref34" ]
18,614,536
pmid-8662797|NA|pmid-17018293
Interestingly, Ubr1 expression is dependent on the STAT3 activity induced by the IL-6/gp130 signaling pathway (34).
[ "40", "33", "34" ]
117
40,212
1
false
Interestingly, Ubr1 expression is dependent on the STAT3 activity induced by the IL-6/gp130 signaling pathway.
[ "34" ]
Interestingly, Ubr1 expression is dependent on the STAT3 activity induced by the IL-6/gp130 signaling pathway.
true
true
true
true
true
6,942
5
DISCUSSION
1
40
[ "ref40", "ref33", "ref34" ]
18,614,536
pmid-8662797|NA|pmid-17018293
We found that Ubr1 was expressed in the OS of the photoreceptor cells, which encouraged us to further pursue the responsibility of Ubr1 for rhodopsin degradation following IL-6 exposure (Fig.
[ "40", "33", "34" ]
194
40,213
0
false
We found that Ubr1 was expressed in the OS of the photoreceptor cells, which encouraged us to further pursue the responsibility of Ubr1 for rhodopsin degradation following IL-6 exposure (Fig.
[]
We found that Ubr1 was expressed in the OS of the photoreceptor cells, which encouraged us to further pursue the responsibility of Ubr1 for rhodopsin degradation following IL-6 exposure (Fig.
true
true
true
true
true
6,942
5
DISCUSSION
1
40
[ "ref40", "ref33", "ref34" ]
18,614,536
pmid-8662797|NA|pmid-17018293
Moreover, Ubr1 mRNA expression was significantly up-regulated after LPS injection in the retinas of α-Cre SOCS3flox/flox mice, where STAT3 activation was exaggerated.
[ "40", "33", "34" ]
169
40,214
0
false
Moreover, Ubr1 mRNA expression was significantly up-regulated after LPS injection in the retinas of α-Cre SOCS3flox/flox mice, where STAT3 activation was exaggerated.
[]
Moreover, Ubr1 mRNA expression was significantly up-regulated after LPS injection in the retinas of α-Cre SOCS3flox/flox mice, where STAT3 activation was exaggerated.
true
true
true
true
true
6,942
5
DISCUSSION
1
40
[ "ref40", "ref33", "ref34" ]
18,614,536
pmid-8662797|NA|pmid-17018293
Thus, SOCS3 may contribute to photoreceptor cell protection during retinal inflammation by inhibiting the expression of the UPS-related gene, Ubr1, through suppression of STAT3 activation.
[ "40", "33", "34" ]
190
40,215
0
false
Thus, SOCS3 may contribute to photoreceptor cell protection during retinal inflammation by inhibiting the expression of the UPS-related gene, Ubr1, through suppression of STAT3 activation.
[]
Thus, SOCS3 may contribute to photoreceptor cell protection during retinal inflammation by inhibiting the expression of the UPS-related gene, Ubr1, through suppression of STAT3 activation.
true
true
true
true
true
6,942