Projects Offered
Dorothee Dormann René Ketting Edward Lemke Katja Luck_Comp Katja Luck_BAF Johannes Mayer_Activate Johannes Mayer_DCTraining Sandra Schick_Cond Sandra Schick_BAF1 Vincent ten Cate Ari Waisman/Ilgiz Mufazalov Andreas Walther Eva Wolf Shuqing XuMolecular interactions in the mammalian circadian clock
1 PhD project offered in the IPP winter call 2026/2027
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 protein interactions of PERIOD clock proteins in the context of 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 and is targeted by WDR5 WIN site inhibitors. In this PhD project the interactions between PER1, WDR5 and 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 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 significant previous exposure to theoretical and practical aspects of 3D-structural-, biochemical- and biophysical analyses of proteins and protein complexes during their bachelor/master education and practical experience in relevant techniques.
If you are interested in this project, please select Wolf as your group preference in the IPP application platform.
Publications relevant to the project
Börgel A*, Hof F*, Welzel M, Rawleigh A, Wedemann M, Mororo Cavalcanti Keller R, Maissl V, Ricci K, Schick S, May-Simera HL, Brown S, Kramer A, Luck K, Ripperger JA and Wolf E (2026) Role of PER-WDR5 interactions in the mammalian circadian clock. Accepted.
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
