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Systematic characterization of indel variants using a yeast-based protein folding sensor
Open accessPreprint — published as 10.1016/j.str.2024.11.017 · Paper page
Abstract
Gene variants resulting in insertions or deletions of amino acid residues (indels) have important consequences for evolution and are often linked to disease, yet compared to missense variants the effects of indels are poorly understood and predicted. To approach this issue, we developed a sensitive protein folding sensor based on complementation of uracil auxotrophy in yeast by circular permutated orotate phosphoribosyltransferase (CPOP). The sensor accurately reports on the folding of disease-linked missense variants and de novo designed proteins. Applying the folding sensor to a saturated library of single amino acid indel variants in human DHFR revealed that most regions which tolerate indels are confined to internal loops and the N- and C-termini. Surprisingly, indels are also allowed at a central α-helix. Several indels are temperature-sensitive and the folding of most of these indels is rescued upon binding to the competitive DHFR inhibitor methotrexate. Rosetta and AlphaFold2 predictions correlate with the observed effects, suggesting that most indels operate by destabilizing the native fold and that these computational tools may be useful for classification of indels observed in population sequencing.
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Metadata
- Authors
- Larsen-Ledet, S., Lindemose, S., Panfilova, A., Gersing, S., Suhr, C. H., Genzor, A. V., Lanters, H., Nielsen, S. V., Lindorff-Larsen, K., Winther, J. R., Stein, A., & Hartmann-Petersen, R.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Stein, Amelie
- ORCID
- Venue
- Structure
- Publisher
- openRxiv
- Published
- 2024-07-11
- Volume
- 33
- Issue
- 2
- Pages
- 262-273.e6
- ISSN
- 0969-2126 (ISSN-L)
- OpenAlex
- W4405567688
- Cited by
- 3
- References
- 1
- Citations by year
- 2026: 1 · 2025: 2
- FWCI
- 0.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Structure (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Natur og Univers, Det Frie Forskningsråd
- Københavns Universitet
- Lundbeckfonden (R272-2017-452)
- Danmarks Frie Forskningsfond
- Novo Nordisk Fonden (NNF21OC0071057, NNF18OC0033950)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- indel variants, dihydrofolate reductase, protein stability, temperature sensitivity, protein design, structure prediction, missense mutations
- MeSH terms
- Humans, Methotrexate, Models, Molecular, Orotate Phosphoribosyltransferase, Saccharomyces cerevisiae, Tetrahydrofolate Dehydrogenase, Uracil, Protein Folding, Mutation, Missense, INDEL Mutation
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