spacer SRC SH2 THREF1TRP MUTANT
Primary citation
Title Structural basis for specificity switching of the Src SH2 domain.
Authors Kimber, M.S.search; Nachman, J.search; Cunningham, A.M.search; Gish, G.D.search; Pawson, T.search; Pai, E.F.search
Journal MOL.CELLsearch vol:5, pag:1043-1049 (2000), Identifiers: PubMed ID (10911998)search DOI (10.1016/S1097-2765(00)80269-5)
Abstract The Src SH2 domain binds pYEEI-containing phosphopeptides in an extended conformation with a hydrophobic pocket, which includes ThrEF1, binding Ile(pY +3). Mutating ThrEF1 to tryptophan switches specificity to an Asn(pY +2) requirement, yielding a biological mimic of the Grb2 SH2 domain. Here we show that the Src ThrEF1Trp SH2 domain mutant binds pYVNV phosphopeptides in a beta turn conformation, which, despite differing conformations of the interacting tryptophan, closely resembles the native Grb2/pYVNV cognate peptide binding mode. The ThrEF1Trp substitution therefore switches specificity by physically occluding the pTyr +3 binding pocket and by providing additional interaction surface area for Asn(pY +2). This demonstrates structurally how novel SH2 domain specificities may rapidly evolve through single amino acid substitutions and suggests how new signaling pathways may develop.
MeSH terms Adaptor Proteinssearch, Signal Transducingsearch, Amino Acid Sequencesearch, Amino Acid Substitutionsearch, Animalssearch, Binding Sitessearch, Chickenssearch, Crystallographysearch, X-Raysearch, Evolutionsearch, Molecularsearch, GRB2 Adaptor Proteinsearch, Ligandssearch, Modelssearch, Molecularsearch, Mutationsearch, Phosphopeptidessearch, Protein Bindingsearch, Protein Conformationsearch, Protein-Tyrosine Kinasessearch, Proteinssearch, Signal Transductionsearch, Substrate Specificitysearch, src Homology Domainssearch
Other entries described in this publication 1f1w
spacer