Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16INK4A

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dc.contributor.authorGöbl C
dc.contributor.authorMorris VK
dc.contributor.authorvan Dam L
dc.contributor.authorVisscher M
dc.contributor.authorPolderman PE
dc.contributor.authorHartlmüller C
dc.contributor.authorde Ruiter H
dc.contributor.authorHora M
dc.contributor.authorLiesinger L
dc.contributor.authorBirner-Gruenberger R
dc.contributor.authorVos HR
dc.contributor.authorReif B
dc.contributor.authorMadl T
dc.contributor.authorDansen TB
dc.date.accessioned2019-11-11T01:02:29Z
dc.date.available2019-11-11T01:02:29Z
dc.date.issued2020en
dc.date.updated2019-10-28T21:09:10Z
dc.description.abstractThe tumor suppressor p16INK4A induces cell cycle arrest and senescence in response to oncogenic transformation and is therefore frequently lost in cancer. p16INK4A 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 p16INK4A in human cells occurs under relatively mild oxidizing conditions and leads to disulfide-dependent dimerization. p16INK4A is an all α-helical protein, but we find that upon cysteine-dependent dimerization, p16INK4A 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. p16INK4A 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 p16INK4A through the formation of amyloid fibrils.en
dc.identifier.citationGöbl C, Morris VK, van Dam L, Visscher M, Polderman PE, Hartlmüller C, de Ruiter H, Hora M, Liesinger L, Birner-Gruenberger R, Vos HR, Reif B, Madl T, Dansen TB (2020). Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16INK4A. Redox Biology. 28. 101316-101316.en
dc.identifier.doihttps://doi.org/10.1016/j.redox.2019.101316
dc.identifier.issn2213-2317
dc.identifier.urihttp://hdl.handle.net/10092/17592
dc.languageEnglish
dc.language.isoen
dc.publisherElsevier BVen
dc.rights2213-2317/ © 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).en
dc.subjectamyloidsen
dc.subjectprotein aggregationen
dc.subjectredox signalingen
dc.subjectcysteine oxidationen
dc.subjectstructural biologyen
dc.subject.anzsrcFields of Research::31 - Biological sciences::3101 - Biochemistry and cell biology::310112 - Structural biology (incl. macromolecular modelling)en
dc.titleCysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16INK4Aen
dc.typeJournal Articleen
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