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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.*

Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16(INK4A).

Redox Biol. 28:101316 (2020)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
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The tumor suppressor p16(INK4A) induces cell cycle arrest and senescence in response to oncogenic transformation and is therefore frequently lost in cancer. p16(INK4A) is also known to accumulate under conditions of oxidative stress. Thus, we hypothesized it could potentially be regulated by reversible oxidation of cysteines (redox signaling). Here we report that 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 a-helical protein, but we find 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-beta sheet structure, and typical dimensions found in electron microscopy. p16(INK4A) amyloid formation abolishes its function as a Cyclin Dependent Kinase 4/6 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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Publication type Article: Journal article
Document type Scientific Article
Keywords Amyloids ; Protein Aggregation ; Redox Signaling ; Cysteine Oxidation ; Structural Biology; Disulfide Bonds; Cell-cycle; Protein; Aggregation; Expression; Quantification; Form; Ftir
Language english
Publication Year 2020
Prepublished in Year 2019
HGF-reported in Year 2019
ISSN (print) / ISBN 2213-2317
e-ISSN 2213-2317
Journal Redox Biology
Quellenangaben Volume: 28, Issue: , Pages: , Article Number: 101316 Supplement: ,
Publisher Elsevier
Publishing Place Amsterdam [u.a.]
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-503090-001
G-503000-001
DOI 10.1016/j.redox.2019.101316
WOS ID WOS:000501490700025
Scopus ID 85072193657
PubMed ID 31539802
Erfassungsdatum 2019-10-07
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