| Structural and energetic mechanisms of cooperative autoinhibition and activation of Vav1. | |
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MedLine Citation:
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PMID: 20141838 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Vav proteins are guanine nucleotide exchange factors (GEFs) for Rho family GTPases. They control processes including T cell activation, phagocytosis, and migration of normal and transformed cells. We report the structure and biophysical and cellular analyses of the five-domain autoinhibitory element of Vav1. The catalytic Dbl homology (DH) domain of Vav1 is controlled by two energetically coupled processes. The DH active site is directly, but weakly, inhibited by a helix from the adjacent Acidic domain. This core interaction is strengthened 10-fold by contacts of the calponin homology (CH) domain with the Acidic, pleckstrin homology, and DH domains. This construction enables efficient, stepwise relief of autoinhibition: initial phosphorylation events disrupt the modulatory CH contacts, facilitating phosphorylation of the inhibitory helix and consequent GEF activation. Our findings illustrate how the opposing requirements of strong suppression of activity and rapid kinetics of activation can be achieved in multidomain systems. |
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Authors:
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Bingke Yu; Ilídio R S Martins; Pilong Li; Gaya K Amarasinghe; Junko Umetani; Martin E Fernandez-Zapico; Daniel D Billadeau; Mischa Machius; Diana R Tomchick; Michael K Rosen |
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Publication Detail:
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Type: 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. |
Journal Detail:
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Title: Cell Volume: 140 ISSN: 1097-4172 ISO Abbreviation: Cell Publication Date: 2010 Jan |
Date Detail:
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Created Date: 2010-02-09 Completed Date: 2010-02-25 Revised Date: 2010-12-03 |
Medline Journal Info:
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Nlm Unique ID: 0413066 Medline TA: Cell Country: United States |
Other Details:
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Languages: eng Pagination: 246-56 Citation Subset: IM |
Copyright Information:
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Copyright 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Department of Biochemistry, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8816, USA. |
| Data Bank Information | |
Bank Name/Acc. No.:
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PDB/3KY9 |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Crystallography, X-Ray Kinetics Models, Molecular Protein Structure, Tertiary Proto-Oncogene Proteins c-vav / chemistry* Thermodynamics |
| Grant Support | |
ID/Acronym/Agency:
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AI065474/AI/NIAID NIH HHS; CA102721/CA/NCI NIH HHS; CA136526/CA/NCI NIH HHS; GM066930/GM/NIGMS NIH HHS; P50 CA102701-07/CA/NCI NIH HHS; //Howard Hughes Medical Institute; //Howard Hughes Medical Institute |
| Chemical | |
Reg. No./Substance:
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0/Proto-Oncogene Proteins c-vav; 0/VAV1 protein, human; 0/Vav1 protein, mouse |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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