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The mechanism of activation of the actin binding protein EHBP1 by Rab8 family members
Structural highlights
DiseaseEHBP1_HUMAN Disease susceptibility is associated with variants affecting the gene represented in this entry. FunctionEHBP1_HUMAN May play a role in actin reorganization. Links clathrin-mediated endocytosis to the actin cytoskeleton. May act as Rab effector protein and play a role in vesicle trafficking (PubMed:14676205, PubMed:27552051). Required for perinuclear sorting and insulin-regulated recycling of SLC2A4/GLUT4 in adipocytes (By similarity).[UniProtKB:Q69ZW3][1] [2] Publication Abstract from PubMedEHBP1 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. The mechanism of activation of the actin binding protein EHBP1 by Rab8 family members.,Rai A, Bleimling N, Vetter IR, Goody RS Nat Commun. 2020 Aug 21;11(1):4187. doi: 10.1038/s41467-020-17792-3. PMID:32826901[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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