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Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16 INK4A
Open accessPreprint — published as 10.1016/j.redox.2019.101316 · Paper page
Abstract
Accumulation of the CDK4/6 inhibitor p16 INK4A in response to oncogenic transformation leads to cell cycle arrest and senescence and is therefore frequently lost in cancer. p16 INK4A is also known to accumulate under conditions of oxidative stress and thus could potentially be regulated by the reversible oxidation of cysteines (redox signaling). Indeed, oxidation of the single cysteine in p16 INK4A in human cells occurs under relatively mild oxidizing conditions and leads to disulfide-dependent dimerization. p16 INK4A is an all alpha-helical protein, but here we report that upon cysteine-dependent dimerization, p16 INK4A undergoes a dramatic structural rearrangement and forms aggregates that have the typical features of amyloid fibrils, including binding of diagnostic dyes, presence of cross-β sheet structure, and typical dimensions found in electron microscopy. p16 INK4A amyloid formation abolishes its function as a CDK4/6 inhibitor. Collectively, these observations mechanistically link the cellular redox state to the inactivation of p16 INK4A through the formation of amyloid fibrils.
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Metadata
- Authors
- Göbl, C., Morris, V. K., van Dam, L., Visscher, M., Polderman, P. E., Hartlmüller, C., de Ruiter, H., Hora, M., Liesinger, L., Birner-Gruenberger, R., Vos, H. R., Reif, B., Madl, T., & Dansen, T. B.
- Affiliations
- Center for Integrated Protein Science Munich (DE)
- University Medical Center Utrecht (NL)
- Medical University of Graz (AT)
- Corresponding author
- Madl, Tobias
- Dansen, Tobias B.
- ORCID
- Venue
- Redox Biology
- Publisher
- openRxiv
- Published
- 2019-01-02
- Volume
- 28
- Pages
- 101316-101316
- ISSN
- 2213-2317 (ISSN-L)
- PMC
- PMC6812003
- OpenAlex
- W2972098902
- Cited by
- 29
- References
- 75
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 6 · 2023: 2 · 2022: 5 · 2021: 5 · 2020: 6
- FWCI
- 1.32
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Redox Biology (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- UC Research Repository (University of Canterbury) (submittedVersion, cc-by-nc-nd)
- mediaTUM (Technical University of Munich) (submittedVersion, other-oa)
- Site cant be reached (submittedVersion, cc-by-nc-nd)
- Funders
- National Natural Science Foundation of China (KLI645, 31450110423, KLI425)
- Chinese Academy of Sciences (2015VBB045)
- Austrian Science Fund (P28854 and I3792, DK-MCD W1226, KLI645, FWF: P28854, 870454, I 3792, KLI 425, 864690, P28854, W 1226)
- KWF Kankerbestrijding
- Österreichische Forschungsförderungsgesellschaft (864690, 870454, 2016/2017, P28854, W1226, I3792, DK-MCD W1226)
- BioTechMed-Graz (870454, P28854, 864690, 2016/2017, DK-MCD W1226, I3792)
- Medical Research Council
- National Health and Medical Research Council
- Helmholtz Zentrum München
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- p16INK4a, cysteine oxidation, amyloid fibril formation, redox signaling, protein dimerization, disulfide bonds, protein aggregation, cross-β sheet, CDK4/6 inhibition, tumor suppressor inactivation, oxidative stress, protein structural rearrangement
- MeSH terms
- Amyloid, Cell Cycle, Cysteine, Humans, Models, Molecular, Oxidation-Reduction, Cellular Senescence, Protein Structure, Secondary, Cyclin-Dependent Kinase Inhibitor p16, Protein Multimerization, HEK293 Cells
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