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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)
Verlagsversion Forschungsdaten DOI
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Amyloids ; Protein Aggregation ; Redox Signaling ; Cysteine Oxidation ; Structural Biology; Disulfide Bonds; Cell-cycle; Protein; Aggregation; Expression; Quantification; Form; Ftir
ISSN (print) / ISBN 2213-2317
e-ISSN 2213-2317
Zeitschrift Redox Biology
Quellenangaben Band: 28, Heft: , Seiten: , Artikelnummer: 101316 Supplement: ,
Verlag Elsevier
Verlagsort Amsterdam [u.a.]
Begutachtungsstatus Peer reviewed