Structure of BAI1/ELMO2 complex reveals an action mechanism of adhesion GPCRs via ELMO family scaffolds

Zhuangfeng Weng,Zhenguo Wu,Jinwei Zhu,Chenghao Situ,Rongguang Zhang,Lin Lin

doi:10.1038/s41467-018-07938-9

Abstract

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.

Highlights

The brain-specific angiogenesis inhibitor (BAI) subfamily of adhesion G protein-coupled receptors plays crucial roles in diverse cellular processes including phagocytosis, myoblast fusion, and synaptic development through the engulfment and motility (ELMO)/DOCK/Rac signaling pathway, the underlying molecular mechanism is not well understood
These data indicated that the Ras-binding domain (RBD), armadillo repeats domain (ARR), ELMO domains of ELMO2 form a structural and functional supramodule required for BAI1 binding
Despite that the adhesion G protein-coupled receptors (aGPCRs) family is widely linked to enormous important physiological processes and a variety of human diseases, little is known about molecular basis of aGPCR-mediated intracellular signaling

Summary

Introduction

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, the underlying molecular mechanism is not well understood. 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. BAI1 was discovered as an engulfment receptor that can recognize phosphatidylserine, a key eat-me signal exposed on apoptotic cells, and promote the internalization of apoptotic cells through the ELMO/DOCK/Rac signaling module[14]. All of the BAI subfamily members are enriched in the post synaptic density (PSD), a central hub for neuronal signaling transduction in the excitatory synapses[18]. BAIs play essential roles in synaptogenesis and synaptic plasticity at least in part via their interactions with the ELMO scaffolds[20,21]

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Results

Conclusion