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PMID: 21107423 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Structure and control of the actin regulatory WAVE complex.

Nature ·Vol. 468 ·No. 7323 ·2010-11-25 ·Pages 533-8

Chen Z, Borek D, Padrick SB, Gomez TS, Metlagel Z, Ismail AM, Umetani J, Billadeau DD, Otwinowski Z, Rosen MK

Abstract

Members of the Wiskott-Aldrich syndrome protein (WASP) family control cytoskeletal dynamics by promoting actin filament nucleation with the Arp2/3 complex. The WASP relative WAVE regulates lamellipodia formation within a 400-kilodalton, hetero-pentameric WAVE regulatory complex (WRC). The WRC is inactive towards the Arp2/3 complex, but can be stimulated by the Rac GTPase, kinases and phosphatidylinositols. Here we report the 2.3-ångstrom crystal structure of the WRC and complementary mechanistic analyses. The structure shows that the activity-bearing VCA motif of WAVE is sequestered by a combination of intramolecular and intermolecular contacts within the WRC. Rac and kinases appear to destabilize a WRC element that is necessary for VCA sequestration, suggesting the way in which these signals stimulate WRC activity towards the Arp2/3 complex. The spatial proximity of the Rac binding site and the large basic surface of the WRC suggests how the GTPase and phospholipids could cooperatively recruit the complex to membranes.

MeSH Terms
Actins/metabolism Animals HeLa Cells Humans Insecta/cytology Models, Molecular Phosphorylation Protein Structure, Quaternary Wiskott-Aldrich Syndrome Protein Family/chemistry rac1 GTP-Binding Protein/metabolism
Chemicals
Actins Wiskott-Aldrich Syndrome Protein Family rac1 GTP-Binding Protein
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Chen Zhucheng
Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
Borek Dominika
Padrick Shae B
Gomez Timothy S
Metlagel Zoltan
Ismail Ayman M
Umetani Junko
Billadeau Daniel D
Otwinowski Zbyszek
Rosen Michael K
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature09623
Published
2010-11-25
Pages
533-8
Language
English
Region
England
NLM ID
0410462
PMCID
PMC3085272
Subset
IM
Grants
NIAID NIH HHS · R01-AI065474 · United States
NIAID NIH HHS · R01 AI065474 · United States
NIGMS NIH HHS · R01-GM053163 · United States
NIAID NIH HHS · AI07047 · United States
NIGMS NIH HHS · R01-GM056322 · United States
NIGMS NIH HHS · 1F32-GM06917902 · United States
NIGMS NIH HHS · R01 GM053163 · United States
Howard Hughes Medical Institute · United States
NIGMS NIH HHS · R01 GM056322-15 · United States
NIAID NIH HHS · T32 AI007047 · United States
NIGMS NIH HHS · R01 GM056322 · United States
Databases
PDB
3P8C
External Links
PubMed source DOI: 10.1038/nature09623 PMC Full Text View journal details
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