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首页> 外文期刊>Biochemistry >Structural and molecular characterization of a preferred protein interaction surface on G protein beta gamma subunits
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Structural and molecular characterization of a preferred protein interaction surface on G protein beta gamma subunits

机译：G蛋白βγ亚基上优选蛋白质相互作用表面的结构和分子表征

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G protein beta gamma subunits associate with many binding partners in cellular signaling cascades. In previous work, we used random-peptide phage display screening to identify a diverse family of peptides that bound to a common surface on G beta gamma subunits and blocked a subset of G beta gamma effectors. Later studies showed that one of the peptides caused G protein activation through a novel G beta gamma-dependent, nucleotide exchange-independent mechanism. Here we report the X-ray crystal structure of G beta(1)gamma(2) bound to this peptide, SIGK (SIGKAFKILGYPDYD), at 2.7 angstrom resolution. SIGK forms a helical structure that binds the same face of Get as the switch II region of G alpha. The interaction interface can be subdivided into polar and nonpolar interfaces that together contain a mixture of binding determinants that may be responsible for the ability of this surface to recognize multiple protein partners. Systematic mutagenic analysis of the peptide-G alpha gamma interface indicates that distinct sets of amino acids within this interface are required for binding of different peptides. Among these unique amino acid interactions, specific electrostatic binding contacts within the polar interface are required for peptide-mediated subunit dissociation. The data provide a mechanistic basis for multiple target recognition by G alpha gamma subunits with diverse functional interactions within a common interface and suggest that pharmacological targeting of distinct regions within this interface could allow for selective manipulation of G beta gamma-dependent signaling pathways.
机译：G蛋白βγ亚基与细胞信号级联反应中的许多结合伴侣相关。在以前的工作中，我们使用随机肽噬菌体展示筛选来鉴定与Gβγ亚基的公共表面结合并阻断Gβγ效应子的一个肽的多样化家族。后来的研究表明，其中一种肽通过一种新颖的Gβγ依赖性，核苷酸交换非依赖性机制引起G蛋白活化。在这里，我们报告以2.7埃分辨率与该肽SIGK（SIGKAFKILGYPDYD）结合的G beta（1）gamma（2）的X射线晶体结构。 SIGK形成一个螺旋结构，该结构绑定了与G alpha的switch II区域相同的Get面。相互作用界面可以细分为极性和非极性界面，它们一起包含可能导致该表面识别多种蛋白质伴侣能力的结合决定簇的混合物。肽-Gαγ界面的系统诱变分析表明，该界面内不同的氨基酸集对于结合不同的肽是必需的。在这些独特的氨基酸相互作用中，肽介导的亚基解离需要极性界面内的特定静电结合接触。数据为共同接口内具有多种功能相互作用的Gαγ亚基识别多个靶标提供了机械基础，并表明该接口内不同区域的药理靶向可允许选择性操纵Gβγ依赖性信号传导途径。

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