Document Detail


Simultaneous binding of two peptidyl ligands by a SRC homology 2 domain.
MedLine Citation:
PMID:  21800896     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Src homology 2 (SH2) domains mediate protein-protein interactions by recognizing phosphotyrosine (pY)-containing sequences of target proteins. In all of the SH2 domain-pY peptide interactions described to date, the SH2 domain binds to a single pY peptide. Here, determination of the cocrystal structure of the N-terminal SH2 domain of phosphatase SHP-2 bound to a class IV peptide (VIpYFVP) revealed a noncanonical 1:2 (protein-peptide) complex. The first peptide binds in a canonical manner with its pY side chain inserted in the usual binding pocket, while the second pairs up with the first to form two antiparallel β-strands that extend the central β-sheet of the SH2 domain. This unprecedented binding mode was confirmed in the solution phase by NMR experiments and shown to be adopted by pY peptides derived from cellular proteins. Site-directed mutagenesis and surface plasmon resonance studies revealed that the binding of the first peptide is pY-dependent, but phosphorylation is not required for the second peptide. Our findings suggest a potential new function for the SH2 domain as a molecular clamp to promote dimerization of signaling proteins.
Authors:
Yanyan Zhang; Jinjin Zhang; Chunhua Yuan; Ryan L Hard; In-Hee Park; Chenglong Li; Charles Bell; Dehua Pei
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2011-08-09
Journal Detail:
Title:  Biochemistry     Volume:  50     ISSN:  1520-4995     ISO Abbreviation:  Biochemistry     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-08-30     Completed Date:  2011-10-21     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7637-46     Citation Subset:  IM    
Affiliation:
Ohio State Biochemistry Program, The Ohio State University, Columbus, Ohio 43210, United States.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Crystallography, X-Ray
Ligands
Mice
Molecular Sequence Data
Mutagenesis, Site-Directed
Peptide Fragments / chemistry*,  genetics,  metabolism*
Phosphorylation / genetics
Phosphotyrosine / chemistry,  metabolism
Protein Binding / physiology
Protein Structure, Secondary / genetics
Protein Structure, Tertiary / genetics
Surface Plasmon Resonance
src Homology Domains / genetics,  physiology*
Grant Support
ID/Acronym/Agency:
CA132855/CA/NCI NIH HHS; GM062820/GM/NIGMS NIH HHS; GM08512/GM/NIGMS NIH HHS; R01 CA132855-03/CA/NCI NIH HHS; R01 GM062820-08/GM/NIGMS NIH HHS; T32 GM008512-15/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Ligands; 0/Peptide Fragments; 21820-51-9/Phosphotyrosine
Comments/Corrections
Erratum In:
Biochemistry. 2011 Oct 4;50(39):8519

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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