The mechanism of activation of the actin binding protein EHBP1 by Rab8 family members

Amrita Rai (), Nathalie Bleimling, Ingrid R. Vetter and Roger S. Goody ()
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Amrita Rai: Max Planck Institute of Molecular Physiology
Nathalie Bleimling: Max Planck Institute of Molecular Physiology
Ingrid R. Vetter: Max Planck Institute of Molecular Physiology
Roger S. Goody: Max Planck Institute of Molecular Physiology

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract EHBP1 is an adaptor protein that regulates vesicular trafficking by recruiting Rab8 family members and Eps15-homology domain-containing proteins 1/2 (EHD1/2). It also links endosomes to the actin cytoskeleton. However, the underlying molecular mechanism of activation of EHBP1 actin-binding activity is unclear. Here, we show that both termini of EHBP1 have membrane targeting potential. EHBP1 associates with PI(3)P, PI(5)P, and phosphatidylserine via its N-terminal C2 domain. We show that in the absence of Rab8 family members, the C-terminal bivalent Mical/EHBP Rab binding (bMERB) domain forms an intramolecular complex with its central calponin homology (CH) domain and auto-inhibits actin binding. Rab8 binding to the bMERB domain relieves this inhibition. We have analyzed the CH:bMERB auto-inhibited complex and the active bMERB:Rab8 complex biochemically and structurally. Together with structure-based mutational studies, this explains how binding of Rab8 frees the CH domain and allows it to interact with the actin cytoskeleton, leading to membrane tubulation.

Date: 2020
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DOI: 10.1038/s41467-020-17792-3

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