二聚体Rasip1 RA结构域识别GTP结合蛋白Ras亚家族的结构基础
Structural Basis of Dimeric Rasip1 RA Domain Recognition of the Ras Subfamily of GTP-Binding Proteins.
作者信息
Gingras Alexandre R, Puzon-McLaughlin Wilma, Bobkov Andrey A, Ginsberg Mark H
机构信息
Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
出版信息
Structure. 2016 Dec 6;24(12):2152-2162. doi: 10.1016/j.str.2016.10.001. Epub 2016 Nov 10.
Ras-interacting protein 1 (Rasip1) is an endothelial-specific Rap1 and Ras effector, important for vascular development and angiogenesis. Here, we report the crystal structure of the Rasip1 RA domain (RRA) alone, revealing the basis of dimerization, and in complex with Rap1 at 2.8 Å resolution. In contrast to most RA domains, RRA formed a dimer that can bind two Rap1 (K = 0.9 μM) or Ras (K = 2.2 μM) molecules. We solved the Rap1-RRA complex and found that Rasip1 binds Rap1 in the Switch I region, and Rap1 binding induces few conformation changes to Rasip1 stabilizing a β strand and an unstructured loop. Our data explain how Rasip1 can act as a Rap1 and Ras effector and show that Rasip1 defines a subgroup of dimeric RA domains that could mediate cooperative binding to membrane-associated Ras superfamily members.
Ras相互作用蛋白1（Rasip1）是一种内皮细胞特异性的Rap1和Ras效应蛋白，对血管发育和血管生成至关重要。在此，我们报告了单独的Rasip1 RA结构域（RRA）的晶体结构，揭示了其二聚化的基础，并以2.8埃的分辨率解析了其与Rap1的复合物结构。与大多数RA结构域不同，RRA形成了一个可以结合两个Rap1（K = 0.9 μM）或Ras（K = 2.2 μM）分子的二聚体。我们解析了Rap1-RRA复合物结构，发现Rasip1在开关I区域结合Rap1，并且Rap1的结合仅引起Rasip1少量的构象变化，从而稳定了一条β链和一个无规环。我们的数据解释了Rasip1如何作为Rap1和Ras效应蛋白发挥作用，并表明Rasip1定义了一个二聚体RA结构域亚组，该亚组可能介导与膜相关的Ras超家族成员的协同结合。
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