Projects Offered
Dorothee Dormann René Ketting Edward Lemke Stamatis Papathanasiou Eva Wolf Johannes Mayer_Ageing Johannes Mayer_Dynamics Daniel Sasca Natalia Soshnikova Tim Sparwasser Ari WaismanMolecular interactions in the mammalian circadian clock
1 PhD project offered in the IPP summer call Molecular Mechanisms in Genome Stability & Gene Regulation
Scientific background
Many physiological processes are regulated in a day-time dependent (circadian) manner. In the primary gene regulatory feedback loop of the mammalian circadian clock, the transcription factors CLOCK and BMAL1 activate the expression of PERIOD (PER1,2,3) and Cryptochrome (CRY1,2) clock proteins, which feedback-repress CLOCK/BMAL1. Within a 24h day, CLOCK/BMAL1 cycles between an active state recruiting co-activators like MLL1, an early repressed state including CRY1/2, PER, CK1 kinase and other proteins, and a late repressed state where only CRY1 remains associated with CLOCK/BMAL1. Additionally, cytosolic CRY/PER/CK1 containing complexes are formed before the proteins enter the nucleus in a time-regulated manner. In a secondary feedback loop, the circadian expression of Bmal1 is regulated by the nuclear receptors REV-ERB and ROR.
PhD project: 3D structural and molecular mechanistic analyses of PERIOD protein interactions in the mammalian circadian clock
This PhD project aims to characterize the dynamically changing protein interactions of PERIOD clock proteins in the context of cytosolic or nuclear PER/CRY/CK1 containing complexes, employing in vitro protein biochemistry, high resolution 3D structure determination by X-ray crystallography or Cryo-EM, quantitative/biophysical protein interaction studies, spectroscopy and molecular biology. We recently showed that WDR5, a component of the CLOCK/BMAL1 co-activating MLL1 histone-methyltransferase complex, also forms a PER1/WDR5 complex, that affects circadian oscillations (publication under revision). In this PhD project the interactions between PER1, WDR5 and the REV-ERB/ROR nuclear receptors will be further investigated on a molecular mechanistic and 3D structural level to understand how the PER1/WDR5 complex impacts the primary and secondary feedback loop of the mammalian circadian clock. The PhD candidate will also further investigate the interaction interplay of PERIOD proteins with other protein components of CRY/PER/CK1 containing complexes. We are looking for a highly motivated PhD candidate with a strong interest in structural biology of proteins, protein biochemistry- and biophysics, and significant previous exposure to these areas during their bachelor/master education.
If you are interested in this project, please select Wolf as your group preference in the IPP application platform.
Publications relevant to the project
Schmalen I, Reischl S, Wallach T, Klemz R, Grudziecki A, Prabu JR, Benda C, Kramer A and Wolf E (2014) Interaction of circadian clock proteins CRY1 and PER2 is modulated by zinc binding and disulfide bond formation. Cell, 157:1203–1215, doi: 10.1016/j.cell.2014.03.057. Link
Kucera N, Schmalen I, Hennig S, Ollinger R, Strauss HM, Grudziecki A, Wieczorek C, Kramer A and Wolf E (2012) Unwinding the differences of the mammalian PERIOD clock proteins from crystal structure to cellular function.Proc Natl Acad Sci USA, 109:3311–3316, doi: 10.1073/pnas.1113280109. Link
Hennig S, Strauss HM, Vanselow K, Yildiz O, Schulze S, Arens J, Kramer A and Wolf E (2009) Structural and functional analyses of PAS domain interactions of the clock proteins Drosophila PERIOD and mouse PERIOD2. PLOS Biol, 7:e94. doi: 10.1371/journal.pbio.1000094. Link
