Structural and Energetic Mechanisms of Cooperative Autoinhibition and Activation of Vav1
Open accessAbstract
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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In the Rho GEF proto-oncogene VAV1, autoinhibition is mediated by interactions involving its atypical C1 and calponin homology (CH) domains.
“For instance, in the Rho GEF proto-oncogene VAV1, such autoinhibition is mediated by interactions involving its atypical C1 and calponin homology (CH) domains.33”
From Structural basis of microtubule-mediated signal transduction (2026) · cites this paper as [33]
The Introduction and Results (pages unavailable in our copy) show that CH-domain interactions strengthen Vav1 autoinhibition. But the Results describe the inhibitory contacts as involving the CH, Acidic, PH and DH regions, and explicitly state that the CH domain does not contact the zinc-finger domain; they do not establish the claimed involvement of an atypical C1 domain in those inhibitory interactions. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNone of the EOM models showed a specific interaction between the C1 and DH-PH domains as seen in the autoinhibited VAV1 DH-PH-C1 structure, and SEC-MALS experiments did not find an interaction between C1 and DH-PH.
“none of these models showed a specific interaction between the C1 and DH-PH domains, as seen in the autoinhibited VAV1 DH-PH-C1 structure.”
From Structural basis of microtubule-mediated signal transduction (2026) · cites this paper as [33]
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- Authors
- Yu, B., Martins, I. R. S., Li, P., Amarasinghe, G. K., Umetani, J., Fernandez-Zapico, M. E., Billadeau, D. D., Machius, M., Tomchick, D. R., & Rosen, M. K.
- Affiliations
- Howard Hughes Medical Institute (US)
- The University of Texas Southwestern Medical Center (US)
- Mayo Clinic (US)
- Corresponding author
- Rosen, Michael K.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2010-01
- Volume
- 140
- Issue
- 2
- Pages
- 246-256
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2825156
- OpenAlex
- W2160438933
- Cited by
- 156
- References
- 0
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 4 · 2023: 10 · 2022: 5 · 2021: 7 · 2020: 11 · 2019: 9 · 2018: 11 · 2017: 9 · 2016: 8 · 2015: 5 · 2014: 13 · 2013: 14 · 2012: 17
- FWCI
- 6.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Department of Energy
- Cancer Research Institute
- Leukemia and Lymphoma Society
- National Institutes of Health
- National Cancer Institute (CA102721, P20CA102701, CA 136526, P50CA102701, R01CA136526)
- National Institute of General Medical Sciences (GM066930, R01GM066930)
- National Institute of Allergy and Infectious Diseases (AI065474, R01AI065474)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK084567)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- Vav1, guanine nucleotide exchange factor, Rho GTPases, autoinhibition, cooperative activation, Dbl homology domain, calponin homology domain, pleckstrin homology domain, acidic domain, phosphorylation, protein structure
- MeSH terms
- Kinetics, Models, Molecular, Thermodynamics, Protein Structure, Tertiary, Crystallography, X-Ray, Proto-Oncogene Proteins c-vav
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