EPFL BioEngineering Talks

Weekly BioEngineering Talks (Lunch Provided)

INVITED SPEAKER:

Building Time: Switching Circadian Clock Complexes through Clustered Hyperphosphorylation of Intrinsically Disordered Regions
Prof. Michael Brunner, Heidelberg University Biochemistry Center (BZH)
Host: Prof. Felix Naef

Abstract:
Circadian clocks generate ~24 h rhythms through delayed negative feedback, yet how progressive phosphorylation of clock proteins is translated into temporally ordered molecular events remains incompletely understood. In the mammalian clock, PERIOD (PER) proteins form complexes with CRYPTOCHROME (CRY) and casein kinase 1δ (CK1δ) and undergo extensive phosphorylation within intrinsically disordered regions over the circadian cycle.
We identify a molecular principle by which progressive phosphorylation can generate distinct and persistent regulatory states. Whereas individual phosphosites are rapidly dephosphorylated, multisite phosphoclusters within disordered regions of PER2 become resistant to phosphatases and display switch-like, all-or-none phosphorylation. Distinct phosphoclusters, including the FASP region, the β-TrCP phosphodegron, and a C-terminal phosphocluster, exhibit markedly different dephosphorylation kinetics.
Together, these findings suggest that progressive phosphorylation of intrinsically disordered PER2 is decoded by phosphoclusters that function as molecular switches with distinct kinetic properties. Their sequential accumulation may generate a series of metastable functional states, thereby translating progressive phosphorylation into circadian control of subunit remodeling, subcellular localization, and turnover of repressor complexes.

Bio:
Michael Brunner is Professor of Biochemistry at Heidelberg University and a leading researcher in the molecular mechanisms of circadian clocks. He received his PhD from Heidelberg University in 1989, followed by postdoctoral research with James E. Rothman at Princeton University and the Sloan Kettering Institute, and with Walter Neupert at Ludwig Maximilian University of Munich. During this time, he made important contributions to mitochondrial biology, particularly to elucidating the molecular machinery responsible for mitochondrial protein import. He joined the Heidelberg University Biochemistry Center (BZH) as a professor in 2000 and has served several terms in its academic leadership, including as Director of the BZH. He is currently Editor-in-Chief of FEBS Letters.

Brunner’s research has contributed to one of the most complete molecular descriptions of biological timekeeping in any organism. Using the filamentous fungus Neurospora crassa, his laboratory has elucidated central features of the circadian feedback loop, including the functions of the White Collar Complex and FREQUENCY, and the roles of casein kinase 1, progressive phosphorylation, and dynamic complex remodelling in determining circadian period and timing. In parallel, his group has extended this work to human cells, investigating the coordination of the circadian clock with the cell cycle and cellular proliferation. Notably, this research has revealed mechanisms through which oncogenic pathways such as MYC can suppress the molecular clock and promote proliferation, thereby linking circadian regulation to malignant growth. His broader work examines how circadian systems respond to environmental and metabolic signals and how clock function may influence cancer biology and treatment.

STUDENT SPEAKER:

FluidFM: A new tool for Lipid Droplet research
Geoffray Marie-Devillard, Deplancke Lab


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