Structural biology of circadian clock proteins
1 PhD project offered in the IPP summer call 2019
Many physiological and behavioral processes are regulated in a day-time dependent (circadian) manner. Circadian clocks evolved to enhance fitness by allowing organisms to anticipate daily environmental changes such as the light-dark cycle. Disruption of circadian cycles due to mutations, jet-lag or shift-work can severely compromise physiology and human health. Circadian rhythms are generated by endogenous circadian clocks, which are operated by gene regulatory feedback loops. In mammals, the BMAL1/CLOCK transcription factor complex regulates the expression of three period (PER1,2,3) and two cryptochrome (CRY1,2) clock genes as well as many clock controlled genes. BMAL1/CLOCK activity is critically regulated by its temporally changing association with different co-activators or co-repressors and by circadian changes in chromatin modification. Our goal is to acquire an atomic resolution picture and quantitative mechanistic understanding of the molecular processes governing circadian gene regulation. We therefore use a highly interdisciplinary structural biology approach, which includes 3D-structural (mostly X-ray crystallography), biochemical and biophysical studies on purified clock proteins as well as structure-based functional studies in cell culture and living organisms.
To elucidate the molecular mechanisms underlying circadian gene regulation and its adaptive evolution, the PhD student will structurally and functionally characterize clock proteins applying a wide range of techniques including recombinant protein expression, protein purification, X-ray crystallography, biochemical and biophysical protein interaction studies and molecular biology. Within collaborations, she/he will also analyze protein interactions using cell-based- and proteomics approaches. Furthermore, clock protein function and evolution will be addressed by collaborative behavioral and phylogenetic analyses. Candidates with a strong interest in structural biology, protein biochemistry, protein structure-function relationship and evolutionary biology and a significant previous exposure to these research areas during their master education are encouraged to apply.
Publications relevant to these projects
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, May 22;157(5):1203–1215.
Czarna A, Berndt A, Singh HR, Grudziecki A, Ladurner A, Timinszky G, Kramer A, and Wolf E (2013). Structures of Drosophila Cryptochrome and mouse Cryptochrome1 provide insight into circadian function. Cell, Jun 6;153(6):1394-405.
Kucera N, Schmalen I, Hennig S, Öllinger 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. PNAS, Feb 28;109(9):3311-6.
Czarna A, Breitkreuz H, Mahrenholz CC, Arens J, Strauss HM and Wolf E (2011). Quantitative analyses of Cryptochrome - mBMAL1 interactions: mechanistic insights into the transcriptional regulation of the mammalian circadian clock. JBC, Jun 24;286(25):22414-25.