Simultaneous Binding of Two Peptidyl Ligands by a Src Homology 2 Domain

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• 作者：Yanyan Zhang ; Jinjin Zhang ; Chunhua Yuan ; Ryan L. Hard ; In-Hee Park ; Chenglong Li ; Charles Bell ; Dehua Pei
• 刊名：Biochemistry
• 出版年：2011
• 出版时间：September 6, 2011
• 年：2011
• 卷：50
• 期：35
• 页码：7637-7646
• 全文大小：435K
• 年卷期：v.50,no.35(September 6, 2011)
• ISSN：1520-4995

文摘

Src homology 2 (SH2) domains mediate protein鈥損rotein interactions by recognizing phosphotyrosine (pY)-containing sequences of target proteins. In all of the SH2 domain鈥損Y 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鈥損eptide) 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 尾-strands that extend the central 尾-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.