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

Mutsuko Kukimoto-Niino1, Kazushige Katsura1, Rahul Kaushik1

  • 1RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.

Science Advances
|July 22, 2021
PubMed

Insights

The ELMO1-DOCK5 complex structure reveals how Engulfment and cell motility (ELMO) proteins regulate Rac activation. This finding offers insights into cell motility and cancer metastasis mechanisms.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Structural Biology

Background:

  • Dedicator of cytokinesis (DOCK) proteins are guanine nucleotide exchange factors (GEFs) crucial for cell motility and cancer metastasis.
  • Engulfment and cell motility (ELMO) proteins interact with DOCK proteins to regulate Rac GTPase activity.

Purpose of the Study:

  • To determine the cryo-electron microscopy structure of the active ELMO1-DOCK5 complex bound to Rac1.
  • To elucidate the structural basis for ELMO-mediated regulation of DOCK GEF activity and Rac selectivity.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) at 3.8-Å resolution.
  • Protein complex structural analysis.
  • Site-directed mutagenesis studies.

Main Results:

  • The structure reveals a complex scaffold between ELMO1 and DOCK5 stabilizing nucleotide-free Rac1.
  • The C-terminal region of ELMO1, including its pleckstrin homology (PH) domain, is essential for DOCK5-Rac1 interaction.
  • Mutagenesis confirms the PH domain of ELMO1 enhances DOCK5 GEF activity via specific Rac1 interactions.

Conclusions:

  • The ELMO1-DOCK5 structure provides key insights into the mechanism of Rac activation by DOCK GEFs.
  • ELMO proteins modulate DOCK biochemical activity and confer Rac selectivity.
  • Understanding this complex is vital for targeting cell motility pathways in cancer metastasis.

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