Cryo-EM structure of the human ELMO1-DOCK5-Rac1 complex

Mutsuko Kukimoto-Niino, Kazushige Katsura, Rahul Kaushik, Haruhiko Ehara, Takeshi Yokoyama, Tomomi Uchikubo-Kamo, Reiko Nakagawa, Chiemi Mishima-Tsumagari, Mayumi Yonemochi, Mariko Ikeda, Kazuharu Hanada, Kam Y.J. Zhang, Mikako Shirouzu

Research output: Contribution to journalArticlepeer-review

Abstract

The dedicator of cytokinesis (DOCK) family of guanine nucleotide exchange factors (GEFs) promotes cell motility, phagocytosis, and cancer metastasis through activation of Rho guanosine triphosphatases. Engulfment and cell motility (ELMO) proteins are binding partners of DOCK and regulate Rac activation. Here, we report the cryo-electron microscopy structure of the active ELMO1-DOCK5 complex bound to Rac1 at 3.8-Å resolution. The C-terminal region of ELMO1, including the pleckstrin homology (PH) domain, aids in the binding of the catalytic DOCK homology region 2 (DHR-2) domain of DOCK5 to Rac1 in its nucleotide-free state. A complex α-helical scaffold between ELMO1 and DOCK5 stabilizes the binding of Rac1. Mutagenesis studies revealed that the PH domain of ELMO1 enhances the GEF activity of DOCK5 through specific interactions with Rac1. The structure provides insights into how ELMO modulates the biochemical activity of DOCK and how Rac selectivity is achieved by ELMO.

Original languageEnglish
Article numbereabg3147
JournalScience Advances
Volume7
Issue number30
DOIs
Publication statusPublished - 2021 Jul

ASJC Scopus subject areas

  • General

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