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Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activation
0
Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activation Panagis Filippakopoulos,1,8Michael Kofler,2,8Oliver Hantschel,3,8Gerald D. Gish,2,8Florian Grebien,3Eidarus Salah,1 Philipp Neudecker,4Lewis E. Kay,4Benjamin E. Turk,5Giulio Superti-Furga,3,*Tony Pawson,2,6,*and Stefa...
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kinase sh2 domain fes tyrosine domains substrate abl recognition university fps toronto kinases catalytic activity active interactions oxford structural activation
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Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activation
1
membrane association and oligomerization mediated by the F-BAR domain and by recruitment to specific subcellular sites by the SH2 domain ( Brooks-Wilson et al., 1989; Naba et al., 2008; Read et al., 1997; Tsujita et al., 2006 ). The N-terminal Gag sequences of v-Fps/Fes oncoproteins result in more stable membrane locali...
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sh2 kinase domain fes active domains substrate fps structure activation terminal region figure structures conformation phosphorylation greer catalytic two tyrosine
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Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activation
2
SH2-kinase interface on human Fes activity. To this end, we monitored Fes autophosphorylation and transphosphorylation activity in transfected cells, using cortactin (residues 382–550)fused to GST as an exogenous substrate ( Figures 2 A and 2B). In an effort to perturb the close interaction between the SH2 and kinase d...
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kinase sh2 fes domain interface activity mutant helix mutations fps structural domains human figures e472 electrostatic figure cortactin residues mutated
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Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activation
3
In summary, the residues at the SH2-kinase domain interface stabilize an active conformation of the Fes kinase domain, inpart by positioning and stabilizing helix aC to form the active site. Substrate Binding and an Antiparallel bSheet Stabilize the Fes Activation Segment To better understand Fes regulation, we also so...
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fes activation kinase substrate sh2 active segment domain peptide figure residues tyrosine binding bsheet phosphorylated kinases interactions flag anti panel
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Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activation
4
sequence preferentially recognized by the Fes active site (Figure S7 ). The two screens revealed that Fes prefers substrates with bulky aliphatic residues at the position N terminal to the sub- strate tyrosine (position /C01), an acidic or phosphorylated residue at position +1, and hydrophobic residues at position +3. ...
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sh2 fes domain substrate residues active binding ptyr kinase activation site position figure phosphorylated figures ligand loop high segment shown
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"Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activa(...TRUNCATED)
5
"domain-binding site, linked by a polyglycine spacer of variable\nlength to an unphosphorylated tyro(...TRUNCATED)
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[-0.06775268912315369,-0.44722098112106323,-0.09322696924209595,-0.19570235908031464,0.1372824609279(...TRUNCATED)
"kinase sh2 abl domain activity substrate lobe fes figure nagar tyrosine phosphorylation peptide res(...TRUNCATED)
[0.11022280156612396,-0.5681320428848267,-0.19959218800067902,-0.04248280078172684,0.143803149461746(...TRUNCATED)
"Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activa(...TRUNCATED)
6
"S9D and S9E). HA-tagged Abl proteins were precipitated from\nHEK293 cells and assayed for phosphory(...TRUNCATED)
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[-0.06674288958311081,-0.443125456571579,-0.09188003838062286,-0.18679212033748627,0.139508008956909(...TRUNCATED)
"sh2 domain kinase fes active activation helix substrate abl interactions binding effect figure acti(...TRUNCATED)
[0.028668534010648727,-0.7448766231536865,-0.1550757735967636,-0.23680339753627777,0.101315610110759(...TRUNCATED)
"Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activa(...TRUNCATED)
7
"through a series of linked devices. For one, clustering induces\nintermolecular autophosphorylation(...TRUNCATED)
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[-0.06940232217311859,-0.4536266326904297,-0.09464538097381592,-0.19815759360790253,0.11981225013732(...TRUNCATED)
"kinase abl domain sh2 fes activation substrate activity active domains stabilizes state membrane pt(...TRUNCATED)
[0.1557217836380005,-0.842115581035614,-0.14626534283161163,-0.010230571031570435,0.2113016843795776(...TRUNCATED)
"Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activa(...TRUNCATED)
8
"SH2 domain can direct subcellular localization and substrate re-\ncruitment and promote an active c(...TRUNCATED)
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[-0.08142413944005966,-0.4328019917011261,-0.09554870426654816,-0.183843195438385,0.1405455172061920(...TRUNCATED)
"sh2 kinase domain fes active abl using domains data anti catalytic protein substrate conformation s(...TRUNCATED)
[0.16253094375133514,-0.8001930713653564,-0.19065743684768677,0.050327323377132416,0.216953471302986(...TRUNCATED)
"Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activa(...TRUNCATED)
9
"Data Processing, Molecular Replacement, and Refinement\nData were indexed and integrated using MOS(...TRUNCATED)
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[-0.07736387848854065,-0.4417183995246887,-0.09811335802078247,-0.1873847097158432,0.133638203144073(...TRUNCATED)
"fes cell kinase protein using structure domain 2008 fps 2007 biol tyrosine structural mol src data (...TRUNCATED)
[0.10716253519058228,-0.3093935549259186,-0.20897433161735535,0.03832915797829628,0.1606442034244537(...TRUNCATED)
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