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

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.

Abstract

Brain-specific angiogenesis inhibitor (BAI) is an adhesion G protein-coupled receptor that acts through the ELMO/DOCK/Rac signaling pathway. Here the authors provide molecular insights into BAI/ELMO interactions by solving the crystal structure of the C-terminal cytoplasmic tail of BAI bound to the RAE tandem domains of ELMO2.