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Structural Basis for Autoinhibition by the Dephosphorylated Regulatory Domain of Ycf1
Open accessPreprint — published as 10.1038/s41467-024-46722-w · Paper page
Abstract
Yeast Cadmium Factor 1 (Ycf1) sequesters glutathione and glutathione-heavy metal conjugates into yeast vacuoles as a cellular detoxification mechanism. Ycf1 belongs to the C subfamily of ATP Binding Cassette (ABC) transporters characterized by long flexible linkers, notably the regulatory domain (R-domain). R-domain phosphorylation is necessary for activity, whereas dephosphorylation induces autoinhibition through an undefined mechanism. Because of its transient and dynamic nature, no structure of the dephosphorylated Ycf1 exists, limiting understanding of this R-domain regulation. Here, we capture the dephosphorylated Ycf1 using cryo-EM and show that the unphosphorylated R-domain indeed forms an ordered structure with an unexpected helix-strand hairpin topology bound within the Ycf1 substrate cavity. This architecture and binding mode resemble that of a viral peptide inhibitor of an ABC transporter and the secreted bacterial WXG peptide toxins. We further reveal the subset of phosphorylation sites within the hairpin turn that drive the reorganization of the R-domain conformation, suggesting a mechanism for Ycf1 activation by phosphorylation-dependent release of R-domain mediated autoinhibition.
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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
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Metadata
- Authors
- Khandelwal, N. K., & Tomasiak, T. M.
- Affiliations
- University of Arizona (US)
- Corresponding author
- Tomasiak, Thomas M.
- Venue
- Nature Communications
- Publisher
- openRxiv
- Published
- 2023-06-22
- Volume
- 15
- Issue
- 1
- Pages
- 2389-2389
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC10944535
- OpenAlex
- W4392880833
- Cited by
- 17
- References
- 1
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 5
- FWCI
- 2.90
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- U.S. Department of Energy (grid.436923.9, 436923.9)
- U.S. Department of Health and Human Services (OD011981)
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases (AI156270)
- Oregon Health and Science University (grid.436923.9, 436923.9)
- University of Arizona
- National Institutes of Health (NIH-R01, 1s10od011981-01)
- Office of Science (grid.436923.9)
- National Institute of General Medical Sciences (U24GM129547, OD011981)
- National Institute of Allergy and Infectious Diseases (R01AI156270)
- Biological and Environmental Research (grid.436923.9)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Keywords
- ycf1, ABC transporters, regulatory domain, autoinhibition, dephosphorylation, phosphorylation sites, protein conformational change, Saccharomyces cerevisiae
- MeSH terms
- Cadmium, Glutathione, Peptides, Saccharomyces cerevisiae, ATP-Binding Cassette Transporters, Saccharomyces cerevisiae Proteins
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