Structure of BAI1/ELMO2 complex reveals an action mechanism of adhesion GPCRs via ELMO family scaffolds
Structure of BAI1/ELMO2 complex reveals an action mechanism of adhesion GPCRs via ELMO family scaffolds
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DOI：
10.1038/s41467-018-07938-9
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发表时间：
2019-01
影响因子：
16.6
通讯作者：
Z. Weng;C. Situ;Lin Lin-Lin;Zhenguo Wu;Jinwei Zhu;Rong-guang Zhang
中科院分区：
文献类型：
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作者：
Z. Weng;C. Situ;Lin Lin-Lin;Zhenguo Wu;Jinwei Zhu;Rong-guang Zhang
脑特异性血管生成抑制因子(BAI)亚家族黏附G蛋白偶联受体(AGPCRs)通过Elmo/DOCK/Rac信号通路在多种细胞过程中发挥重要作用，包括吞噬、成肌细胞融合和突触发育，但其潜在的分子机制尚不清楚。在这里，我们证明了位于BAI-aGPCRs的C端细胞质尾部的一个进化保守的片段被Elmo家族支架的RBD-arr-Elmo(RAE)超模块特异性识别。ELMO2-RAE及其与BAI1的络合物的晶体结构揭示了BAI/ELMO相互作用的分子基础。基于复杂的结构，我们确定aGPCR-GPR128是Elmo家族支架的另一个上游受体，很可能具有类似于BAI/Elmo相互作用的识别模式。最后，我们绘制了BAI和Elmo的致病突变图谱，并分析了它们对复合体形成的影响。
The brain-specific angiogenesis inhibitor (BAI) subfamily of adhesion G protein-coupled receptors (aGPCRs) plays crucial roles in diverse cellular processes including phagocytosis, myoblast fusion, and synaptic development through the ELMO/DOCK/Rac signaling pathway, although the underlying molecular mechanism is not well understood. Here, we demonstrate that an evolutionarily conserved fragment located in the C-terminal cytoplasmic tail of BAI-aGPCRs is specifically recognized by the RBD-ARR-ELMO (RAE) supramodule of the ELMO family scaffolds. The crystal structures of ELMO2-RAE and its complex with BAI1 uncover the molecular basis of BAI/ELMO interactions. Based on the complex structure we identify aGPCR-GPR128 as another upstream receptor for the ELMO family scaffolds, most likely with a recognition mode similar to that of BAI/ELMO interactions. Finally, we map disease-causing mutations of BAI and ELMO and analyze their effects on complex formation.