p63 uses a switch-like mechanism to set the threshold for induction of apoptosis.
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
26
06
2019
accepted:
25
06
2020
pubmed:
29
7
2020
medline:
15
12
2020
entrez:
29
7
2020
Statut:
ppublish
Résumé
The p53 homolog TAp63α is the transcriptional key regulator of genome integrity in oocytes. After DNA damage, TAp63α is activated by multistep phosphorylation involving multiple phosphorylation events by the kinase CK1, which triggers the transition from a dimeric and inactive conformation to an open and active tetramer that initiates apoptosis. By measuring activation kinetics in ovaries and single-site phosphorylation kinetics in vitro with peptides and full-length protein, we show that TAp63α phosphorylation follows a biphasic behavior. Although the first two CK1 phosphorylation events are fast, the third one, which constitutes the decisive step to form the active conformation, is slow. Structure determination of CK1 in complex with differently phosphorylated peptides reveals the structural mechanism for the difference in the kinetic behavior based on an unusual CK1/TAp63α substrate interaction in which the product of one phosphorylation step acts as an inhibitor for the following one.
Identifiants
pubmed: 32719556
doi: 10.1038/s41589-020-0600-3
pii: 10.1038/s41589-020-0600-3
doi:
Substances chimiques
TP63 protein, human
0
Transcription Factors
0
Tumor Suppressor Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1078-1086Subventions
Organisme : CIHR
Pays : Canada
Organisme : Wellcome Trust
Pays : United Kingdom
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