25-30 August 2019
Henry Ford Building
Europe/Berlin timezone

NMR investigation of the activation mechanism of the guardian of the germ cell TAp63a

27 Aug 2019, 10:30
35m
Max Kade Auditorium (Henry Ford Building)

Max Kade Auditorium

Henry Ford Building

Invited talk Biological applications Biomolecules

Speaker

Prof. Volker Dötsch (Goethe University)

Description

Cell fate decisions like cell division or apoptosis require cells to translate signals into a final yes/no answer. Primary oocytes are a special type of cells that are arrested in prophase of meiosis I in which they last for up to 50 years in humans. The number of primary oocytes determines the reproductive capacity of females. Due to the importance and the long arrest time of these cells they have evolved a special type of genetic quality control not present in somatic cells. Regulating this control mechanism is of very high importance: Tight genetic quality control is necessary to maintain the genetic integrity of the entire species but a too stringent mechanism can deplete the whole primary oocyte pool leading to infertility. In female germs cells this genetic quality is monitored by the p53 homolog TAp63α. After DNA damage it gets activated by phosphorylation triggering the transition from a closed dimeric state to an open tetramer. We have used NMR spectroscopy to investigate how phosphorylation determines the critical threshold level for elimination of a primary oocyte. Through measuring single site phosphorylation kinetics in isolated peptides as well as in full-length protein we show that phosphorylation follows a biphasic behavior. We reveal the structural mechanism and show by quantitative simulation that the slow phase determines the threshold of DNA damage that is necessary to induce apoptosis.

Primary authors

Dr Jakob Gebel (Goethe University) Dr Marcel Tuppi (The Francis Crick Institute) Dr Apirat Chaikuad (Goethe University) Dr Katharina Hötte (Goethe University) Mrs Laura Schulz (Max Planck Institute for Biophysics) Dr Frank Löhr (Goethe University) Mr Niklas Gutfreund (Goethe University) Dr Ralf Lehnert (Mathezentrum, Goethe University) Prof. Gerhard Hummer (Max Planck Institute for Biophysics) Prof. Ernst Stelzer (Goethe University) Prof. Stefan Knapp (Goethe University) Prof. Volker Dötsch (Goethe University)

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