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TitleStructures reveal a key mechanism of WAVE regulatory complex activation by Rac1 GTPase.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 5444, Year 2022
Publish dateSep 16, 2022
AuthorsBojian Ding / Sheng Yang / Matthias Schaks / Yijun Liu / Abbigale J Brown / Klemens Rottner / Saikat Chowdhury / Baoyu Chen /
PubMed AbstractThe Rho-family GTPase Rac1 activates the WAVE regulatory complex (WRC) to drive Arp2/3 complex-mediated actin polymerization in many essential processes. Rac1 binds to WRC at two distinct sites-the ...The Rho-family GTPase Rac1 activates the WAVE regulatory complex (WRC) to drive Arp2/3 complex-mediated actin polymerization in many essential processes. Rac1 binds to WRC at two distinct sites-the A and D sites. Precisely how Rac1 binds and how the binding triggers WRC activation remain unknown. Here we report WRC structures by itself, and when bound to single or double Rac1 molecules, at ~3 Å resolutions by cryogenic-electron microscopy. The structures reveal that Rac1 binds to the two sites by distinct mechanisms, and binding to the A site, but not the D site, drives WRC activation. Activation involves a series of unique conformational changes leading to the release of sequestered WCA (WH2-central-acidic) polypeptide, which stimulates the Arp2/3 complex to polymerize actin. Together with biochemical and cellular analyses, the structures provide a novel mechanistic understanding of how the Rac1-WRC-Arp2/3-actin signaling axis is regulated in diverse biological processes and diseases.
External linksNat Commun / PubMed:36114192 / PubMed Central
MethodsEM (single particle)
Resolution3.0 Å
Structure data

26732

7usc

EMDB-26732, PDB-7usc:
Cryo-EM structure of WAVE Regulatory Complex
Method: EM (single particle) / Resolution: 3.0 Å

26733

7usd

EMDB-26733, PDB-7usd:
Cryo-EM structure of D-site Rac1-bound WAVE Regulatory Complex
Method: EM (single particle) / Resolution: 3.0 Å

26734

7use

EMDB-26734, PDB-7use:
Cryo-EM structure of WAVE regulatory complex with Rac1 bound on both A and D site
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

ChemComp-GTP:
GUANOSINE-5'-TRIPHOSPHATE / GTP, energy-carrying molecule*YM

ChemComp-MG:
Unknown entry

ChemComp-GNP:
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GppNHp, GMPPNP, energy-carrying molecule analogue*YM

Source
  • homo sapiens (human)
KeywordsCELL INVASION / actin regulator / GTPase binding protein / cytoskeletal regulator

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