FARP2 鸟嘌呤核苷酸交换因子自身抑制的结构基础
Structural basis for autoinhibition of the guanine nucleotide exchange factor FARP2.
机构信息
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75063, USA.
出版信息
Structure. 2013 Mar 5;21(3):355-64. doi: 10.1016/j.str.2013.01.001. Epub 2013 Jan 31.
Abstract
FARP2 is a Dbl-family guanine nucleotide exchange factor (GEF) that contains a 4.1, ezrin, radixin and moesin (FERM) domain, a Dbl-homology (DH) domain and two pleckstrin homology (PH) domains. FARP2 activates Rac1 or Cdc42 in response to upstream signals, thereby regulating processes such as neuronal axon guidance and bone homeostasis. How the GEF activity of FARP2 is regulated remained poorly understood. We have determined the crystal structures of the catalytic DH domain and the DH-PH-PH domains of FARP2. The structures reveal an auto-inhibited conformation in which the GEF substrate-binding site is blocked collectively by the last helix in the DH domain and the two PH domains. This conformation is stabilized by multiple interactions among the domains and two well-structured inter-domain linkers. Our cell-based activity assays confirm the suppression of the FARP2 GEF activity by these auto-inhibitory elements.
摘要
FARP2 是一种 Dbl 家族鸟嘌呤核苷酸交换因子（GEF），包含 4.1、埃兹蛋白、radixin 和 moesin（FERM）结构域、Dbl 同源（DH）结构域和两个pleckstrin 同源（PH）结构域。FARP2 响应上游信号激活 Rac1 或 Cdc42，从而调节神经元轴突导向和骨稳态等过程。FARP2 的 GEF 活性如何被调节仍知之甚少。我们已经确定了 FARP2 的催化 DH 结构域和 DH-PH-PH 结构域的晶体结构。这些结构揭示了一种自动抑制构象，其中 GEF 底物结合位点被 DH 结构域的最后一个螺旋和两个 PH 结构域共同阻断。这种构象通过各个结构域之间的多种相互作用以及两个结构良好的结构域间接头稳定。我们基于细胞的活性测定证实了这些自动抑制元件对 FARP2 GEF 活性的抑制作用。
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