Template-free prediction of a new monotopic membrane protein fold and assembly by AlphaFold2
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Abstract
AlphaFold2 (AF2) has revolutionized the field of protein structural prediction. Here, we test its ability to predict the tertiary and quaternary structure of a previously undescribed scaffold with new folds and unusual architecture, the monotopic membrane protein caveolin-1 (CAV1). CAV1 assembles into a disc-shaped oligomer composed of 11 symmetrically arranged protomers, each assuming an identical new fold, and contains the largest parallel β-barrel known to exist in nature. Remarkably, AF2 predicts both the fold of the protomers and the interfaces between them. It also assembles between seven and 15 copies of CAV1 into disc-shaped complexes. However, the predicted multimers are energetically strained, especially the parallel β-barrel. These findings highlight the ability of AF2 to correctly predict new protein folds and oligomeric assemblies at a granular level while missing some elements of higher-order complexes, thus positing a new direction for the continued development of deep-learning protein structure prediction approaches.
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- Authors
- Gulsevin, A., Han, B., Porta, J. C., Mchaourab, H. S., Meiler, J., & Kenworthy, A. K.
- Affiliations
- Vanderbilt University (US)
- University of Virginia (US)
- University of Michigan (US)
- Corresponding author
- Meiler, Jens
- Kenworthy, Anne K.
- Venue
- Biophysical Journal
- Publisher
- Elsevier BV
- Published
- 2023-06
- Volume
- 122
- Issue
- 11
- Pages
- 2041-2052
- ISSN
- 0006-3495 (ISSN-L)
- PMC
- PMC10257013
- OpenAlex
- W4308559963
- Cited by
- 16
- References
- 46
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 4 · 2022: 2
- FWCI
- 1.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biophysical Journal (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- NHLBI (R01HL122010, R01 HL144131)
- NIGMS (R01GM080403, R01GM129261)
- Alexander von Humboldt-Stiftung
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Machine Learning in Bioinformatics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- caveolin-1, protein fold prediction, quaternary structure prediction, oligomerization, protein-protein interfaces, deep learning protein structure prediction, AlphaFold2
- MeSH terms
- Furylfuramide, Membrane Proteins, Protein Conformation, Protein Structure, Tertiary, Protein Subunits
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