期刊
NATURE CHEMICAL BIOLOGY
卷 16, 期 10, 页码 1078-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41589-020-0600-3
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资金
- DFG [DO 545/18-1]
- Centre for Biomolecular Magnetic Resonance (BMRZ)
- Cluster of Excellence Frankfurt (Macromolecular Complexes)
- German Chemical Industry
- Max Planck Society
- EU Horizon2020 project LSFM4LIFE [668350-2]
- ZonMw-BMBF [114027003]
- Canadian Institutes for Health Research
- Canadian Foundation for Innovation
- Genome Canada through the Ontario Genomics Institute
- GlaxoSmithKline
- Karolinska Institute
- Knut and Alice Wallenberg Foundation
- Ontario Innovation Trust
- Ontario Ministry for Research and Innovation
- Merck Co.
- Novartis Research Foundation
- Swedish Agency for Innovation Systems
- Swedish Foundation for Strategic Research
- Wellcome Trust
The p53 homolog TAp63 alpha is the transcriptional key regulator of genome integrity in oocytes. After DNA damage, TAp63 alpha 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 TAp63 alpha 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/TAp63 alpha substrate interaction in which the product of one phosphorylation step acts as an inhibitor for the following one.
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