Publication Date:
2010-11-26
Description:
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-angstrom 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085272/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085272/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Zhucheng -- Borek, Dominika -- Padrick, Shae B -- Gomez, Timothy S -- Metlagel, Zoltan -- Ismail, Ayman M -- Umetani, Junko -- Billadeau, Daniel D -- Otwinowski, Zbyszek -- Rosen, Michael K -- 1F32-GM06917902/GM/NIGMS NIH HHS/ -- AI07047/AI/NIAID NIH HHS/ -- R01 AI065474/AI/NIAID NIH HHS/ -- R01 GM053163/GM/NIGMS NIH HHS/ -- R01 GM056322/GM/NIGMS NIH HHS/ -- R01 GM056322-15/GM/NIGMS NIH HHS/ -- R01-AI065474/AI/NIAID NIH HHS/ -- R01-GM053163/GM/NIGMS NIH HHS/ -- R01-GM056322/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Nov 25;468(7323):533-8. doi: 10.1038/nature09623.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21107423" target="_blank"〉PubMed〈/a〉
Keywords:
Actins/*metabolism
;
Animals
;
HeLa Cells
;
Humans
;
Insects/cytology
;
*Models, Molecular
;
Phosphorylation
;
Protein Structure, Quaternary
;
Wiskott-Aldrich Syndrome Protein Family/*chemistry
;
rac1 GTP-Binding Protein/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
