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Molecular exaptation by the integrin αI domain
Open accessPublished version of a preprint
Abstract
Integrins bind ligands between their alpha (α) and beta (β) subunits and transmit signals through conformational changes. Early in chordate evolution, some α subunits acquired an “inserted” (I) domain that expanded integrin’s ligand-binding repertoire but obstructed the ancestral ligand pocket, seemingly blocking conventional integrin activation. Here, we compare cryo–electron microscopy structures of apo and ligand-bound states of the I domain–containing αEβ 7 integrin and the I domain–lacking α 4 β 7 integrin to illuminate how the I domain intrinsically mimics an extrinsic ligand to preserve integrin function. We trace the I domain’s evolutionary origin to an ancestral collagen-collagen interaction domain, identifying an ancient molecular exaptation that facilitated integrin activation immediately upon I domain insertion. Our analyses reveal the evolutionary and biochemical basis of expanded cellular communication in vertebrates.
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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
Harnessing protein folding neural networks for peptide–protein docking
Tsaban, T., Varga, J. K., Avraham, O., Ben-Aharon, Z., Khramushin, A., & Schueler-Furman, O. (2022) · Nature Communications · doi:10.1038/s41467-021-27838-9 · Cited by 1,205
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Schenkel, J. M., & Masopust, D. (2014) · Immunity · doi:10.1016/j.immuni.2014.12.007 · Cited by 1,059
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Jamali, K., Käll, L., Zhang, R., Brown, A., Kimanius, D., & Scheres, S. H. W. (2023) · doi:10.1101/2023.05.16.541002 · Cited by 686
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Metadata
- Authors
- Hollis, J. A., Chan, M. C., Malik, H. S., & Campbell, M. G.
- Affiliations
- University of Washington (US)
- Fred Hutch Cancer Center (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Campbell, Melody G.
- Venue
- Science Advances
- Published
- 2025-09-12
- Volume
- 11
- Issue
- 37
- Pages
- eadx9567-eadx9567
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC12422189
- OpenAlex
- W4414110356
- Cited by
- 4
- References
- 6
- Citations by year
- 2026: 2 · 2025: 2
- FWCI
- 3.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Science Advances (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed Central (submittedVersion, cc-by)
- Funders
- National Science Foundation (P30 CA015704, T32GM008268, CA015704)
- Howard Hughes Medical Institute
- National Institutes of Health (CA015704)
- National Cancer Institute (P30CA015704)
- National Institute of General Medical Sciences (T32GM008268, R35GM147414)
- Topics
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- integrin activation, alphaEbeta7 integrin, alpha4beta7 integrin, ligand binding, chordate evolution, signal transduction
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