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Rac1 Selectively Binds a Specific Lamellipodin Isoform via a Noncanonical Helical Interface
Open accessPreprint — published as 10.1016/j.jbc.2025.111023 · Paper page
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 (CC) 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 classical helical pair configuration. Our results reveal a novel isoform-dependent GTPase:effector binding mode and suggest a critical regulatory pathway that may represent a promising therapeutic target in Rac1-driven cancer progression.
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Highly accurate protein structure prediction with AlphaFold
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Metadata
- 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
- openRxiv
- Published
- 2025-06-25
- Volume
- 302
- Issue
- 1
- Pages
- 111023-111023
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC12797038
- OpenAlex
- W4417085639
- Cited by
- 2
- References
- 1
- 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
- American Cancer Society
- Pennsylvania Department of Health (4100085739, ACS RSG-15-167-01-DMC)
- National Institutes of Health
- National Institute of General Medical Sciences (GM119560, R35GM119560)
- 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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