Multiple random phosphorylations in clock proteins provide long delays and switches.

Abhishek Upadhyay, Daniela Marzoll, Axel Diernfellner, Michael Brunner, Hanspeter Herzel

Scientific reports 2020 Dec 17

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Theory predicts that self-sustained oscillations require robust delays and nonlinearities (ultrasensitivity). Delayed negative feedback loops with switch-like inhibition of transcription constitute the core of eukaryotic circadian clocks. The kinetics of core clock proteins such as PER2 in mammals and FRQ in Neurospora crassa is governed by multiple phosphorylations. We investigate how multiple, slow and random phosphorylations control delay and molecular switches. We model phosphorylations of intrinsically disordered clock proteins (IDPs) using conceptual models of sequential and distributive phosphorylations. Our models help to understand the underlying mechanisms leading to delays and ultrasensitivity. The model shows temporal and steady state switches for the free kinase and the phosphoprotein. We show that random phosphorylations and sequestration mechanisms allow high Hill coefficients required for self-sustained oscillations.

Citation

Abhishek Upadhyay, Daniela Marzoll, Axel Diernfellner, Michael Brunner, Hanspeter Herzel. Multiple random phosphorylations in clock proteins provide long delays and switches. Scientific reports. 2020 Dec 17;10(1):22224