Noguchi Hiroki, Ikegami Takahisa, Nagadoi Aritaka, Kamatari Yuji O, Park Sam-Yong, Tame Jeremy R H, Unzai Satoru
Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro, Yokohama, Kanagawa 230-0045, Japan.
Life Science Research Center, Gifu University, Gifu 501-1194, Japan.
Biochem Biophys Res Commun. 2015 Jun 19;462(1):46-51. doi: 10.1016/j.bbrc.2015.04.103. Epub 2015 Apr 29.
Rap1B is a small GTPase involved in the regulation of numerous cellular processes including synaptic plasticity, one of the bases of memory. Like other members of the Ras family, the active GTP-bound form of Rap1B can bind to a large number of effector proteins and so transmit signals to downstream components of the signaling pathways. The structure of Rap1B bound only to a nucleotide has yet to be solved, but might help reveal an inactive conformation that can be stabilized by a small molecule drug. Unlike other Ras family proteins such as H-Ras and Rap2A, Rap1B crystallizes in an intermediate state when bound to a non-hydrolyzable GTP analog. Comparison with H-Ras and Rap2A reveals conservative mutations relative to Rap1B, distant from the bound nucleotide, which control how readily the protein may adopt the fully activated form in the presence of GTP. High resolution crystallographic structures of mutant proteins show how these changes may influence the hydrogen bonding patterns of the key switch residues.
Rap1B是一种小GTP酶，参与包括突触可塑性（记忆的基础之一）在内的众多细胞过程的调控。与Ras家族的其他成员一样，活性的GTP结合形式的Rap1B可以与大量效应蛋白结合，从而将信号传递至信号通路的下游组分。仅与核苷酸结合的Rap1B的结构尚未解析，但这可能有助于揭示一种可被小分子药物稳定的无活性构象。与其他Ras家族蛋白如H-Ras和Rap2A不同，Rap1B在与不可水解的GTP类似物结合时以中间状态结晶。与H-Ras和Rap2A的比较揭示了相对于Rap1B的保守突变，这些突变远离结合的核苷酸，它们控制着蛋白质在GTP存在下采用完全激活形式的难易程度。突变蛋白的高分辨率晶体结构显示了这些变化可能如何影响关键开关残基的氢键模式。
