PXD012353

PXD012353 is an original dataset announced via ProteomeXchange.

Title	Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16INK4A
Description	p16INK4A inhibits the CDK4/6 kinases and is therefore an important cell cycle regulator. Accumulation of p16INK4A in response to oncogenic transformation leads to cellular senescence and it is therefore frequently lost in cancer. p16INK4A is also known to accumulate under conditions of cellular oxidative stress and therefore could potentially be regulated by redox signaling, which is a form of signal transduction that is mediated by the reversible oxidation of cysteine-thiol side chains in proteins. We found that oxidation of the single cysteine residue in p16INK4A in human cells occurs under relatively mild oxidizing conditions and that this leads to disulfide dependent dimerization. p16INK4A is a well-characterized all alpha-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. We find that p16INK4A amyloid formation abolishes its function as a CDK4/6 inhibitor in human cells. Taken together, these observations mechanistically link the cellular redox state to the inactivation of p16INK4A through the formation of amyloid fibrils.
HostingRepository	PRIDE
AnnounceDate	2019-10-25
AnnouncementXML	Submission_2019-10-25_04:52:23.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Harmjan Vos
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2019-01-15 07:36:22	ID requested
1	2019-09-04 01:32:33	announced
⏵ 2	2019-10-25 04:52:24	announced	2019-10-25: Updated publication reference for PubMed record(s): 31539802.

G, ö, bl C, Morris VK, van Dam L, Visscher M, Polderman PE, Hartlm, ü, ller C, de Ruiter H, Hora M, Liesinger L, Birner-Gruenberger R, Vos HR, Reif B, Madl T, Dansen TB, . Redox Biol, 28():101316(2020) [pubmed]

curator keyword: Biomedical

submitter keyword: Cysteine oxidation amyloid fibril p16INK4A

Tobias B. Dansen
contact affiliation	Center for Molecular Medicine, Molecular Cancer Research, University Medical Center Utrecht, Universiteitsweg 100, 3584CG Utrecht, The Netherlands.
contact email	T.B.Dansen@umcutrecht.nl
lab head
Harmjan Vos
contact affiliation	University Medical Center Utrecht Dept. Molecular Cancer Research
contact email	h.r.vos-3@umcutrecht.nl
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2019/09/PXD012353

PRIDE project URI

• PRIDE
  1. PXD012353
     1. Label: PRIDE project
     2. Name: Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16INK4A