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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.

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Fig. 1: TAp63α-mediated PF death follows an overall sigmoidal kinetics.
Fig. 2: The third CK1 phosphorylation is the slowest step in the phosphorylation of a p63-derived peptide (PAD).
Fig. 3: The third CK1 phosphorylation is the slowest step in the TAp63α phosphorylation and constitutes the ‘point of no return’.
Fig. 4: Crystal structures of CK1δ in complexes with different PAD peptides.
Fig. 5: MD simulations indicate that E593 and V589 of the p63 peptide are important for interaction with CK1.
Fig. 6: The interaction affinity between CK1 and PAD peptides does not depend on the phospho-state, but KM values differ by more than an order of magnitude.

Data availability

All data are fully available upon request. PDB accession codes for the three crystal structures are 6RU6, 6RU7 and 6RU8.

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Acknowledgements

We thank I. Theofel, S. Young and E. Chih-Chao Liang for their review of and input into this manuscript. The research was funded by the DFG (DO 545/18-1), the Centre for Biomolecular Magnetic Resonance (BMRZ) and the Cluster of Excellence Frankfurt (Macromolecular Complexes). M.T. was supported by a Fellowship from the fund of the German Chemical Industry. L.S. and G.H. were supported by the Max Planck Society. F.P., K.H. and E.H.K.S. thank the EU Horizon2020 project LSFM4LIFE (grant no. 668350-2) and the ZonMw-BMBF joint sponsored project ‘The Onconoid Hub’ (grant no. 114027003) for funding. The Structural Genomics Consortium is a registered charity (no. 1097737) that receives funds from the Canadian Institutes for Health Research, the Canadian Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, Karolinska Institute, the Knut and Alice Wallenberg Foundation, the Ontario Innovation Trust, the Ontario Ministry for Research and Innovation, Merck & Co., the Novartis Research Foundation, the Swedish Agency for Innovation Systems, the Swedish Foundation for Strategic Research and the Wellcome Trust.

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Contributions

J.G. and M.T. performed NMR and kinetic assays in vitro and in ovaries. A.C. crystallized and solved the structures of the kinase–peptide complexes. K.H. and F.P. performed microscopy experiments and quantitative semi-automated segmentation. L.S. carried out MD simulations. F.L. performed NMR experiments. N.G. measured tetramerization kinetics. F.F., E.H. and J.M. expressed and purified proteins. M.S. measured phosphorylation kinetics. R.L. helped to analyze the data. M.T., G.H., E.H.K.S., S.K. and V.D. designed experiments and analyzed data. J.G., M.T., A.C. and V.D. wrote the manuscript.

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Correspondence to Marcel Tuppi or Volker Dötsch.

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Extended data

Extended Data Fig. 1 Phosphorylation kinetics of the PAD peptide.

Phosphorylation kinetics of the PAD peptide. a, Overlay of HSQC spectra of unphosphorylated (cyan) and MK2 phosphorylated PAD peptide (red). A large chemical shift change in S582 can be observed as a result of phosphorylation. b, Phosphorylation kinetics of S582 pre-phosphorylated PAD peptide (250 µM) and 12.5 nM CK1 kinase. The phosphorylation of S585 (red) is faster compared to the S588 phosphorylation (yellow) to the extent that the pS582/pS585 intermediate state (cyan) is populated to >1000x of the kinase concentration. c, Phosphorylation kinetics of S582, S585, and S588 pre-phosphorylated PAD peptide (250 µM) with 2.5 µM CK1 kinase. The phosphorylation of S591 (red) is faster than T594 (yellow). The difference is smaller, but the concentration of the intermediate state is at least 4x larger than the kinase concentration. d, Overlay of [15 N, 1H]-HSQC spectra of a pS582/S585A PAD peptide (red) and the same peptide after 500 min of exposure to CK1 (blue, 1:2000 kinase:substrate ratio, 25 °C). Only partial phosphorylation of a single residue in the vicinity of S582 is visible, indicated by the splitting of the signal, accounting for 45% of the population of S582. e, f, Overlay of [15 N, 1H]-HSQC spectra of a pS582/S588A PAD peptide (red) and the same peptide after 500 min of exposure to CK1 and phosphorylation kinetics, demonstrating that S585 and T586 are the only residues phosphorylated by CK1 when the second phosphorylation site for CK1 is eliminated. g, Mutation of T586 to alanine does not change the biphasic behavior of the CK1 phosphorylation of the PAD peptide. All experiments were repeated twice and reproducible. Only one replicate is shown in each case.

Extended Data Fig. 2 Phosphorylation kinetics of PAD peptide mutants.

Phosphorylation kinetics of PAD peptide mutants. a, Phosphorylation kinetics of selected PAD mutants showing a reduction in the kinetic difference between S588 and S591. b, Measured kinetic constants for the phosphorylation of S588 (k2) and S591 (k3) in wild type and different mutant PAD peptides as well as the constants for the second and third phosphorylation event in the YAP1 peptide. Measurements were repeated twice under identical conditions. Individual data points are shown. The height of the bar represents the mean value and single measurements are indicated. The phosphorylation kinetics of YAP was measured once.

Extended Data Fig. 3 Crystallographic details.

Crystallographic details. ac, Binding of the PAD peptides within CK1δ in the crystal structures. |Fo | -|Fc| omitted electron density map contoured at three-sigma for the bound PAD peptides. df, Detailed interactions at the N termini of the PAD peptides within the kinase.

Extended Data Fig. 4 MD simulation and kinetics with CK1 mutants.

MD simulation and kinetics with CK1 mutants. a, MD simulation of CK1 in complex with a shorter PAD-3P peptide (ACE-TPpSSApSTVpSVGSSETRG-NME) with N-terminal acetyl and C-terminal methylamino capping groups showing similar results as the longer peptide (Fig. 5a, b). b, Snapshot at 1 µs, zooming in on the C-terminal region of the shorter p63 peptide. CK1 is shown as a transparent electrostatic surface (blue/red for positive/negative charge) and the p63 peptide is represented as a cyan cartoon. The residues E593, Arg127 and Lys154 are highlighted. The minimum distances between E593 and the basic residues are indicated. c, Phosphorylation kinetics of wild type and selected CK1δ mutants showing a reduction in the kinetic difference between S588 and S591 compared to the wild type kinase for Lys171Glu and Lys154Glu mutants. For Arg127Glu the kinetics is, however, slower. CK1 amino acids are labeled in three-letter code and PAD residues are labeled in one-letter code. All kinetic experiments involving kinase mutants were measured once.

Extended Data Fig. 5 Measurements of binding affinity and enzyme kinetics.

Measurements of binding affinity and enzyme kinetics. a, Three independent KD measurements for each phosphorylation state of the peptide are shown (see also Fig. 6a and Supplementary Table 3). Values given in Supplementary Table 3 represent mean + /-SD. b, KM/vmax measurements for different phosphorylation reactions were performed in biological triplicates for S585 as well as S588 and duplicates for S591. In all subpanels single experiments are shown individually (see also Fig. 6b and Supplementary Tables 4 and 5). Values given in Supplementary Table 5 represent mean + /-SD. ce, Linearization curves to account for nonlinear ionization behavior of PAD peptides with different phosphorylation states. Linearization curves were determined once.

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Supplementary Figs. 1–4 and Tables 1–5.

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Gebel, J., Tuppi, M., Chaikuad, A. et al. p63 uses a switch-like mechanism to set the threshold for induction of apoptosis. Nat Chem Biol 16, 1078–1086 (2020). https://doi.org/10.1038/s41589-020-0600-3

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