6RU7

Crystal structure of Casein Kinase I delta (CK1d) in complex with double phosphorylated p63 PAD2P peptide

Summary for 6RU7

• Entry DOI: 10.2210/pdb6ru7/pdb
• Descriptor: Casein kinase I isoform delta, Tumor protein 63, ADENOSINE-5'-DIPHOSPHATE, ... (6 entities in total)
• Functional Keywords: ck1 delta, ck1delta, csnk1d, tp63, p63, kinase substrate complex, structural genomics, structural genomics consortium, sgc, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 74221.25

Authors

Chaikuad, A.,Tuppi, M.,Gebel, J.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Dotsch, V.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2019-05-27, release date: 2020-05-13, Last modification date: 2024-10-23)

Primary citation

Gebel, J.,Tuppi, M.,Chaikuad, A.,Hotte, K.,Schroder, M.,Schulz, L.,Lohr, F.,Gutfreund, N.,Finke, F.,Henrich, E.,Mezhyrova, J.,Lehnert, R.,Pampaloni, F.,Hummer, G.,Stelzer, E.H.K.,Knapp, S.,Dotsch, V.
p63 uses a switch-like mechanism to set the threshold for induction of apoptosis.
Nat.Chem.Biol., 16:1078-1086, 2020

PubMed Abstract: 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.

PubMed: 32719556
DOI: 10.1038/s41589-020-0600-3

Experimental method

X-RAY DIFFRACTION (2.08 Å)