Auto-inhibition of the Dbl Family Protein Tim by an N-terminal Helical Motif
Open accessAbstract
Dbl-related oncoproteins are guanine nucleotide exchange factors specific for Rho-family GTPases and typically possess tandem Dbl homology (DH) and pleckstrin homology domains that act in concert to catalyze exchange. Because the ability of many Dbl-family proteins to catalyze exchange is constitutively activated by truncations N-terminal to their DH domains, it has been proposed that the activity of Dbl-family proteins is regulated by auto-inhibition. However, the exact mechanisms of regulation of Dbl-family proteins remain poorly understood. Here we show that the Dbl-family protein, Tim, is auto-inhibited by a short, helical motif immediately N-terminal to its DH domain, which directly occludes the catalytic surface of the DH domain to prevent GTPase activation. Similar to the distantly related Vav isozymes, auto-inhibition of Tim is relieved by truncation, mutation, or phosphorylation of the auto-inhibitory helix. A peptide comprising the helical motif inhibits the exchange activity of Tim in vitro. Furthermore, substitutions within the most highly conserved surface of the DH domain designed to disrupt interactions with the auto-inhibitory helix also activate the exchange process.
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Proteins in the related family of GEFs often regulate enzymatic activity through autoinhibitory interactions with regions flanking their DH-PH domains.
“Proteins in the related family of GEFs often regulate enzymatic activity through autoinhibitory interactions with regions flanking their DH-PH domains.32”
From Structural basis of microtubule-mediated signal transduction (2026) · cites this paper as [32]
The Abstract and Discussion show that Tim’s exchange activity is inhibited by a helix immediately N-terminal to its DH domain, and the Discussion describes a similar interaction in Vav proteins. The Abstract says truncation findings in many Dbl-family proteins led to a proposal of autoinhibition, while the Discussion calls similar regulation in Tim’s subgroup likely. The source therefore supports the mechanism and examples, but not the claim that such interactions are established as occurring often across the family. (LLM, conf=0.78)
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Cites
Crystal structure of Rac1 in complex with the guanine nucleotide exchange region of Tiam1
Worthylake, D. K., Rossman, K. L., & Sondek, J. (2000) · Nature · doi:10.1038/35047014 · Cited by 355 · see citing works
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Research works printed but not linked: 12
- [1]1. Wennerberg, K. ∙ Der, C.J. J. Cell Sci. 2004; 117:1301-1312 Crossref Scopus (490) PubMed Google Scholar
- [2]2. Etienne-Manneville, S. ∙ Hall, A. Nature. 2002; 420:629-635 Crossref Scopus (4004) PubMed Google Scholar
- [3]3. Sahai, E. ∙ Marshall, C.J. Nat. Rev. Cancer. 2002; 2:133-142 Crossref Scopus (1256) PubMed Google Scholar
- [4]4. Rossman, K.L. ∙ Der, C.J. ∙ Sondek, J. Nat. Rev. Mol. Cell. Biol. 2005; 6:167-180 Crossref Scopus (1388) PubMed Google Scholar
- [5]5. Yoshizuka, N. ∙ Moriuchi, R. ∙ Mori, T. ... J. Biol. Chem. 2004; 279:43998-44004 Full Text Full Text (PDF) Scopus (49) PubMed Google Scholar
- [6]6. Vanni, C. ∙ Mancini, P. ∙ Gao, Y. ... J. Biol. Chem. 2002; 277:19745-19753 Full Text Full Text (PDF) Scopus (32) PubMed Google Scholar
- [7]7. Lopez-Lago, M. ∙ Lee, H. ∙ Cruz, C. ... Mol. Cell. Biol. 2000; 20:1678-1691 Crossref Scopus (145) PubMed Google Scholar
- [8]8. Zenke, F.T. ∙ Krendel, M. ∙ DerMardirossian, C. ... J. Biol. Chem. 2004; 279:18392-18400 Full Text Full Text (PDF) Scopus (141) PubMed Google Scholar
- [9]9. Schmidt, A. ∙ Hall, A. Genes Dev. 2002; 16:1587-1609 Crossref Scopus (1009) PubMed Google Scholar
- [10]10. Chan, A.M. ∙ McGovern, E.S. ∙ Catalano, G. ... Oncogene. 1994; 9:1057-1063 PubMed Google Scholar
- [11]11. Xie, X. ∙ Chang, S.W. ∙ Tatsumoto, T. ... Cell. Signal. 2005; 17:461-471 Crossref Scopus (30) PubMed Google Scholar
- [12]12. Takai, S. ∙ Chan, A.M. ∙ Yamada, K. ... Cancer Genet. Cytogenet. 1995; 83:87-89
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Structural basis of microtubule-mediated signal transduction
Choi, S. R., Blum, T. B., Giono, M., Roy, B., Vakonakis, I., Schmid, D., Oelgarth, N., Ranganathan, A., Gossert, A. D., Shivashankar, G. V., et al. (2026) · Cell · doi:10.1016/j.cell.2025.11.011 · Cited by 14 · see citing works
- Authors
- Yohe, M. E., Rossman, K. L., Gardner, O. S., Karnoub, A. E., Snyder, J. T., Gershburg, S., Graves, L. M., Der, C. J., & Sondek, J.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Sondek, John
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-05
- Volume
- 282
- Issue
- 18
- Pages
- 13813-13823
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2084617572
- Cited by
- 45
- References
- 1
- Citations by year
- 2025: 2 · 2024: 2 · 2021: 2 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 1 · 2016: 3 · 2015: 3 · 2014: 2 · 2013: 3 · 2012: 2
- FWCI
- 1.99
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- American Cancer Society
- Susan G. Komen for the Cure
- National Institutes of Health (5r01gm062299-08, GM65533)
- National Cancer Institute (CA 92240, CA 063071, R01CA063071, R01CA092240)
- National Institute of General Medical Sciences (GM 65533, GM62299, P01GM065533)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- TIM, autoinhibition, Dbl homology domain, guanine nucleotide exchange factor, Rho GTPases, protein phosphorylation
- MeSH terms
- Animals, Catalysis, Enzyme Activation, Humans, Isoenzymes, Mutation, Recombinant Proteins, Protein Structure, Tertiary, Cell Cycle Proteins, Guanine Nucleotide Exchange Factors, Amino Acid Motifs, Intracellular Signaling Peptides and Proteins, Mice, Proto-Oncogene Proteins c-vav
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