Structural basis for specificity switching of the Src SH2 domain

被引：37

作者：

Kimber, MS

Nachman, J

Cunningham, AM

Gish, GD

Pawson, T

Pai, EF ^{[1
]}

机构：

[1] Univ Toronto, Dept Mol & Med Genet, Toronto, ON M5S 1A8, Canada

[2] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada

[3] Univ Toronto, Dept Med Biophys, Toronto, ON M5S 1A8, Canada

[4] Univ Toronto, Prot Engn Network Ctr Excellence, Toronto, ON M5S 1A8, Canada

[5] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Programme Mol Biol & Canc, Toronto, ON M5G 1X5, Canada

来源：

MOLECULAR CELL | 2000年 / 5卷 / 06期

基金：

英国医学研究理事会;

关键词：

D O I：

10.1016/S1097-2765(00)80269-5

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The Src SH2 domain binds pYEEI-containing phosphopeptides in an extended conformation with a hydrophobic pocket, which includes ThrEF1, binding IIe(pY +3). Mutating ThrEF1 to tryptophan switches specificity to an Asn(pY +2) requirement, yielding a biological mimic of the GrbP SH2 domain. Here we show that the Src ThrEF1TrpSH2 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.

引用

页码：1043 / 1049

页数：7

共 32 条

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