Rac1 selectively binds a specific lamellipodin isoform via a noncanonical helical interface
Open accessPublished version of a preprint
Abstract
Lamellipodin (Lpd) is a multifunctional adapter protein that regulates cell migration and adhesion by recruiting Ena/VASP proteins to the leading edge and modulating actin polymerization. The interaction of Lpd and Rho family or Ras family GTPases is crucial for regulating actin dynamics. Contrary to previous assumptions that the main Lpd isoform interacts with Rac1, here we show that strong and specific binding to Rac1 is instead mediated by the short isoform Lpds. This interaction is dependent on Rac1's GTPase activity and a short insertion (cs2) within the coiled-coil region unique to the Lpds isoform. Structural modeling and mutagenesis analyses further reveal that Lpds engages Rac1 through a noncanonical, single-helix binding mode distinct from the canonical helical-pair configuration. Our results uncover a novel isoform-dependent GTPase:effector binding mode for Rac1-driven actin dynamics, with implications for therapeutic targeting in Rac1-associated cancer progression.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Accurate structure prediction of biomolecular interactions with AlphaFold 3
Abramson, J., Adler, J., Dunger, J., Evans, R., Green, T., Pritzel, A., Ronneberger, O., Willmore, L., Ballard, A. J., Bambrick, J., et al. (2024) · Nature · doi:10.1038/s41586-024-07487-w · Cited by 15,861 · see citing works
Ras protein abundance correlates with Ras isoform mutation patterns in cancer
Hood, F. E., Sahraoui, Y. M., Jenkins, R. E., & Prior, I. A. (2023) · Oncogene · doi:10.1038/s41388-023-02638-1 · Cited by 56 · see citing works
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- Authors
- Gao, T., Zhang, P., Kurimchak, A. M., Duncan, J. S., & Wu, J.
- Affiliations
- Fox Chase Cancer Center (US)
- Corresponding author
- Wu, Jinhua
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2026-01
- Volume
- 302
- Issue
- 1
- Pages
- 111023
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC12797038
- OpenAlex
- W4417085639
- Cited by
- 2
- References
- 3
- Citations by year
- 2026: 2
- FWCI
- 0.60
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Funders
- Pennsylvania Department of Health (4100085739, ACS RSG-15-167-01-DMC)
- American Cancer Society Inc
- National Institutes of Health
- National Institute of General Medical Sciences (GM119560)
- 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 Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- Rac1, lamellipodin, coiled-coil domain, actin dynamics, cell migration, cell adhesion, Ena/VASP proteins, adaptor proteins
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