Quality control in oocytes by p63 is based on a spring-loaded activation mechanism on the molecular and cellular level
Daniel Coutandin,
Christian Osterburg,
Ratnesh Kumar Srivastav,
Manuela Sumyk,
Sebastian Kehrloesser,
Jakob Gebel,
Marcel Tuppi,
Jens Hannewald,
Birgit Schäfer,
Eidarus Salah,
Sebastian Mathea,
Uta Müller-Kuller,
James Doutch,
Manuel Grez,
Stefan Knapp,
Volker Dötsch
Affiliations
Daniel Coutandin
Institute of Biophysical Chemistry, Goethe University, Frankfurt, Germany; Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany; Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany
Christian Osterburg
Institute of Biophysical Chemistry, Goethe University, Frankfurt, Germany; Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany; Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany
Ratnesh Kumar Srivastav
Institute of Biophysical Chemistry, Goethe University, Frankfurt, Germany; Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany; Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany
Manuela Sumyk
Institute of Biophysical Chemistry, Goethe University, Frankfurt, Germany; Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany; Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany
Sebastian Kehrloesser
Institute of Biophysical Chemistry, Goethe University, Frankfurt, Germany; Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany; Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany
Jakob Gebel
Institute of Biophysical Chemistry, Goethe University, Frankfurt, Germany; Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany; Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany
Marcel Tuppi
Institute of Biophysical Chemistry, Goethe University, Frankfurt, Germany; Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany; Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany
Jens Hannewald
MS-DTB-C Protein Purification, Merck KGaA, Darmstadt, Germany
Birgit Schäfer
Institute of Biophysical Chemistry, Goethe University, Frankfurt, Germany; Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany; Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany
Eidarus Salah
Nuffield Department of Medicine, Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom
Sebastian Mathea
Nuffield Department of Medicine, Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom
Uta Müller-Kuller
Georg-Speyer Haus, Frankfurt, Germany
James Doutch
ISIS Neutron and Muon Source, Rutherford Appleton Laboratory, Didcot, United Kingdom
Manuel Grez
Georg-Speyer Haus, Frankfurt, Germany
Stefan Knapp
Nuffield Department of Medicine, Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom; Institute for Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany; Buchmann Institute for Molecular Life Science, Goethe University, Frankfurt, Germany
Institute of Biophysical Chemistry, Goethe University, Frankfurt, Germany; Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany; Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany
Mammalian oocytes are arrested in the dictyate stage of meiotic prophase I for long periods of time, during which the high concentration of the p53 family member TAp63α sensitizes them to DNA damage-induced apoptosis. TAp63α is kept in an inactive and exclusively dimeric state but undergoes rapid phosphorylation-induced tetramerization and concomitant activation upon detection of DNA damage. Here we show that the TAp63α dimer is a kinetically trapped state. Activation follows a spring-loaded mechanism not requiring further translation of other cellular factors in oocytes and is associated with unfolding of the inhibitory structure that blocks the tetramerization interface. Using a combination of biophysical methods as well as cell and ovary culture experiments we explain how TAp63α is kept inactive in the absence of DNA damage but causes rapid oocyte elimination in response to a few DNA double strand breaks thereby acting as the key quality control factor in maternal reproduction.
