Document Detail


Allostery mediates ligand binding to Grb2 adaptor in a mutually exclusive manner.
MedLine Citation:
PMID:  23334917     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Allostery plays a key role in dictating the stoichiometry and thermodynamics of multi-protein complexes driving a plethora of cellular processes central to health and disease. Herein, using various biophysical tools, we demonstrate that although Sos1 nucleotide exchange factor and Gab1 docking protein recognize two non-overlapping sites within the Grb2 adaptor, allostery promotes the formation of two distinct pools of Grb2-Sos1 and Grb2-Gab1 binary signaling complexes in concert in lieu of a composite Sos1-Grb2-Gab1 ternary complex. Of particular interest is the observation that the binding of Sos1 to the nSH3 domain within Grb2 sterically blocks the binding of Gab1 to the cSH3 domain and vice versa in a mutually exclusive manner. Importantly, the formation of both the Grb2-Sos1 and Grb2-Gab1 binary complexes is governed by a stoichiometry of 2:1, whereby the respective SH3 domains within Grb2 homodimer bind to Sos1 and Gab1 via multivalent interactions. Collectively, our study sheds new light on the role of allostery in mediating cellular signaling machinery.
Authors:
Caleb B McDonald; Jimmy El Hokayem; Nawal Zafar; Jordan E Balke; Vikas Bhat; David C Mikles; Brian J Deegan; Kenneth L Seldeen; Amjad Farooq
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of molecular recognition : JMR     Volume:  26     ISSN:  1099-1352     ISO Abbreviation:  J. Mol. Recognit.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-21     Completed Date:  2013-11-12     Revised Date:  2014-02-04    
Medline Journal Info:
Nlm Unique ID:  9004580     Medline TA:  J Mol Recognit     Country:  England    
Other Details:
Languages:  eng     Pagination:  92-103     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 John Wiley & Sons, Ltd.
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing / chemistry*,  genetics
Allosteric Regulation
Amino Acid Motifs
Binding Sites
Escherichia coli / genetics
GRB2 Adaptor Protein / chemistry*,  genetics
Humans
Kinetics
Ligands
Molecular Docking Simulation
Molecular Dynamics Simulation
Molecular Sequence Data
Protein Binding
Protein Interaction Domains and Motifs
Protein Multimerization
Protein Structure, Secondary
Recombinant Proteins / chemistry,  genetics
SOS1 Protein / chemistry*,  genetics
Signal Transduction*
Thermodynamics
Grant Support
ID/Acronym/Agency:
R01 GM083897/GM/NIGMS NIH HHS; R01-GM083897/GM/NIGMS NIH HHS; T32-CA119929/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/GAB1 protein, human; 0/GRB2 Adaptor Protein; 0/GRB2 protein, human; 0/Ligands; 0/Recombinant Proteins; 0/SOS1 Protein
Comments/Corrections

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