p63 uses a switch-like mechanism to set the threshold for induction of apoptosis

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.

Target binding triggers hierarchical phosphorylation of human Argonaute-2 to promote target release

“…CK1α phosphorylation likely occurs in a distributive manner 52 . Because phosphorylation of multiple residues would require CK1α to actively interact with Ago multiple times, supplemental pairing might be expected to increase phosphorylation by way of added affinity.…”

Understanding p53 tumour suppressor network

“…Apoptosis is an ordered and tightly regulated form of cell death and is highly associated to prevention of tumorigenesis. Sequence and homology of p53 are evolutionarily conserved in Drosophila melanogaster (named dmp53 ) and Caenorhabditis elegans (named cep-1 ) [ 1 – 3 ], although debate is still open on whether the mammalian p53 family member, p63 better resembles biochemically and functionally the ancestor form of the protein [ 4 – 10 ]. The response to DNA damage, responsible of activating p53-mediated cell cycle arrest and apoptosis, is a dominant mechanism of p53-mediated network and strongly conserved across species, including Drosophila melanogaster and Caenorhabditis elegans.…”

The Role of Mutant p63 in Female Fertility

“…The first two phosphorylation events are fast, while the third one is the slowest and essential for the formation of the open and active conformation. The decrease in phosphorylation kinetics with higher phosphorylation levels may be due to a decrease in the binding affinity of the increasingly phosphorylated peptide, rendering binding in the substrate-bound position as needed for phosphorylation of S591 as less favorable [34].…”