STRUCTURAL DETERMINANTS OF PEPTIDE-BINDING ORIENTATION AND OF SEQUENCE SPECIFICITY IN SH3 DOMAINS
STRUCTURAL DETERMINANTS OF PEPTIDE-BINDING ORIENTATION AND OF SEQUENCE SPECIFICITY IN SH3 DOMAINS
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DOI：
10.1038/372375a0
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发表时间：
1994-11-24
期刊：
影响因子：
64.8
通讯作者：
FOX, RO
中科院分区：
文献类型：
--
作者：
LIM, WA;RICHARDS, FM;FOX, RO
秀丽隐杆线虫蛋白SEM-5及其人类和果蝇同源物Grb 2和Drk（参考文献1-4）的Src-同源性-3（SH 3）结构域结合核苷酸交换因子Sos中发现的富含脯氨酸的序列，作为它们将受体酪氨酸激酶激活与Ras激活联系起来的功能的一部分（5-7）。在这里，我们报告的晶体结构在2.0埃分辨率的羧基末端SH 3结构域从SEM-5复合到mSos衍生的氨基酸序列PPPVPPRRR。发现肽以与先前在其他SH 3-肽复合物中观察到的方向（“正”方向）完全相反的方向（“负”方向）结合（8，9）。肽识别蛋白以两种不同的模式识别肽的这种新能力可能在涉及SH 3结构域的途径的信号传导特异性中发挥重要作用。这种结构与其他SH 3复合物的比较揭示了保守的结合面如何用于识别不同方向的肽，以及为什么Sos肽以这种特定的方向结合。
THE Src-homology-3 (SH3) domains of the Caenorhabditis elegans protein SEM-5 and its human and Drosophila homologues, Grb2 and Drk (refs 1-4), bind proline-rich sequences found in the nucleotide-exchange factor Sos as part of their proposed function linking receptor tyrosine kinase activation to Ras activation(5-7). Here we report the crystal structure at 2.0 Angstrom resolution of the carboxy-terminal SH3 domain from SEM-5 complexed to the mSos-derived amino-acid sequence PPPVPPRRR. The peptide is found to bind in an orientation ('minus') that is precisely opposite to that observed previously ('plus' orientation) in other SH3-peptide complexes(8,9). This novel ability of peptide-recognition proteins to recognize peptides in two distinct modes may play an important role in the signalling specificity of pathways involving SH3 domains. Comparison of this structure with other SH3 complexes reveals how a conserved binding face can be used to recognize peptides in different orientations, and why the Sos peptide binds in this particular orientation.