Structure of the DOCK2-ELMO1 complex provides insights into regulation of the auto-inhibited state
Structure of the DOCK2-ELMO1 complex provides insights into regulation of the auto-inhibited state
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DOI：
10.1038/s41467-020-17271-9
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发表时间：
2020-07-10
影响因子：
16.6
通讯作者：
Barford, David
中科院分区：
文献类型：
--
作者：
Chang, Leifu;Yang, Jing;Barford, David
DOCK（dedicator of cytokinesis）蛋白是一种多结构域的鸟嘌呤核苷酸交换因子（GEF），其作用是调节细胞内肌动蛋白的动力学。DOCK蛋白共享催化（DOCKDHR 2）和膜相关（DOCKDHR 1）结构域。结构相关的DOCK 1和DOCK 2 GEF对RAC具有特异性，并且需要埃尔莫（吞噬和细胞运动）蛋白发挥功能。埃尔莫（ELMORBD）的N末端RAS结合结构域（RBD）与RHOG相互作用以调节DOCK 1/2活性。在这里，我们确定的冷冻EM结构的DOCK 2-ELMO 1单独，并作为三元复合物与RAC 1，连同晶体结构的RHOG-ELMO 2 RBD复合物。二元DOCK 2-ELMO 1复合物采用封闭的自抑制构象。由于ELMO 1亚基的构象变化，自抑制缓解为活性开放状态，暴露了DOCK 2（DHR 2）上的RAC 1结合位点以及ELMO 1上的RHOG和BAI GPCR。我们的结构解释了上游效应物，包括DOCK 2和ELMO 1磷酸化，如何破坏自抑制状态以促进活跃的GEF。
DOCK (dedicator of cytokinesis) proteins are multidomain guanine nucleotide exchange factors (GEFs) for RHO GTPases that regulate intracellular actin dynamics. DOCK proteins share catalytic (DOCKDHR2) and membrane-associated (DOCKDHR1) domains. The structurally-related DOCK1 and DOCK2 GEFs are specific for RAC, and require ELMO (engulfment and cell motility) proteins for function. The N-terminal RAS-binding domain (RBD) of ELMO (ELMORBD) interacts with RHOG to modulate DOCK1/2 activity. Here, we determine the cryo-EM structures of DOCK2-ELMO1 alone, and as a ternary complex with RAC1, together with the crystal structure of a RHOG-ELMO2RBD complex. The binary DOCK2-ELMO1 complex adopts a closed, auto-inhibited conformation. Relief of auto-inhibition to an active, open state, due to a conformational change of the ELMO1 subunit, exposes binding sites for RAC1 on DOCK2(DHR2), and RHOG and BAI GPCRs on ELMO1. Our structure explains how up-stream effectors, including DOCK2 and ELMO1 phosphorylation, destabilise the auto-inhibited state to promote an active GEF.