p63 uses a switch-like mechanism to set the threshold for induction of apoptosis
| Autor: | Francesco Pampaloni, Volker Dötsch, Erik Henrich, Franziska Finke, Ralf Lehnert, Apirat Chaikuad, Julija Mezhyrova, Laura Schulz, Ernst H. K. Stelzer, Frank Löhr, Jakob Gebel, Stefan Knapp, Katharina Hötte, Martin Schröder, Niklas Gutfreund, Gerhard Hummer, Marcel Tuppi |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
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Models
Molecular inorganic chemicals Time Factors DNA damage Protein Conformation Kinetics Regulator Apoptosis Molecular Dynamics Simulation environment and public health 03 medical and health sciences Mice Tetramer Catalytic Domain ddc:570 Animals Humans Phosphorylation Molecular Biology 030304 developmental biology 0303 health sciences Kinase Chemistry Tumor Suppressor Proteins 030302 biochemistry & molecular biology Cell Biology enzymes and coenzymes (carbohydrates) Structural biology Biophysics Oocytes bacteria Female Casein kinase 1 DNA Damage Transcription Factors |
| Zdroj: | Nature chemical biology 16, 1-19 (2020). doi:10.1038/s41589-020-0600-3 |
| DOI: | 10.1038/s41589-020-0600-3 |
| Popis: | Nature chemical biology 16, 1-19 (2020). doi:10.1038/s41589-020-0600-3 The p53 homolog TAp63$α$ is the transcriptional key regulator of genome integrity in oocytes. After DNA damage, TAp63$α$ 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$α$ 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$α$ substrate interaction in which the product of one phosphorylation step acts as an inhibitor for the following one. Published by Nature Publishing Group, Basingstoke |
| Databáze: | OpenAIRE |
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