Schiering N, Casale E, Caccia P, Giordano P, Battistini C
Department of Structural Chemistry, Discovery Research Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
Biochemistry. 2000 Nov 7;39(44):13376-82. doi: 10.1021/bi0012336.
Src homology 2 (SH2) domains are key modules in intracellular signal transduction. They link activated cell surface receptors to downstream targets by binding to phosphotyrosine-containing sequence motifs. The crystal structure of a Grb2-SH2 domain-phosphopeptide complex was determined at 2.4 A resolution. The asymmetric unit contains four polypeptide chains. There is an unexpected domain swap so that individual chains do not adopt a closed SH2 fold. Instead, reorganization of the EF loop leads to an open, nonglobular fold, which associates with an equivalent partner to generate an intertwined dimer. As in previously reported crystal structures of canonical Grb2-SH2 domain-peptide complexes, each of the four hybrid SH2 domains in the two domain-swapped dimers binds the phosphopeptide in a type I beta-turn conformation. This report is the first to describe domain swapping for an SH2 domain. While in vivo evidence of dimerization of Grb2 exists, our SH2 dimer is metastable and a physiological role of this new form of dimer formation remains to be demonstrated.
Src同源2（SH2）结构域是细胞内信号转导的关键模块。它们通过与含磷酸酪氨酸的序列基序结合，将活化的细胞表面受体与下游靶点相连。Grb2-SH2结构域-磷酸肽复合物的晶体结构在2.4埃分辨率下得以确定。不对称单元包含四条多肽链。存在意想不到的结构域交换，使得单个链不采用封闭的SH2折叠。相反，EF环的重组导致开放的、非球状折叠，其与等效的伙伴缔合以产生缠绕的二聚体。与先前报道的典型Grb2-SH2结构域-肽复合物的晶体结构一样，两个结构域交换二聚体中的四个杂合SH2结构域中的每一个都以I型β-转角构象结合磷酸肽。本报告首次描述了SH2结构域的结构域交换。虽然存在Grb2二聚化的体内证据，但我们的SH2二聚体是亚稳态的，这种新形式的二聚体形成的生理作用仍有待证明。
