Intrinsic Disorder in the Highly-Ordered Circadian Clock

Abstract

The circadian clock, our internal molecular time keeper, regulates everything from blood pressure levels to sleep. Through the ideal programming of behavior, it is believed that the clock enhances fitness by ensuring that many organismal functions are optimally timed with the phase of the circadian day. Conversely, due to the extent of circadian regulation, disruptions of the clock can be harmful; chronic disturbance of the clock leads to an increased risk for heart attack, cancer, diabetes, and mental health disorders among a host of other maladies. The highly conserved mechanism which regulates circadian timing is a molecular transcription-translation negative feedback loop. The core clock complex in the clock model organism Neurospora crassa consists of two sets of protein pairs, the positive arm (comprised of the White Collar 1/ White Collar 2 Complex or WCC) and the negative arm (comprised of the Frequency (FRQ)/Frequency-Interacting RNA Helicase (FRH) complex or FFC). The WCC drives the expression of the FFC, which then regulates its own transcription by inhibiting the activity of the WCC. The FFC is then targeted for degradation, allowing for the reactivation of the WCC, restarting the cycle. My work has shown that intrinsic protein disorder is essential for the proper functioning of this circadian circuit. I have demonstrated that FRQ is an Intrinsically Disordered Protein (IDP); currently, the reason for the IDP nature of FRQ is unknown. In complex with FRQ, FRH stabilizes FRQ and mediates the interactions between the core clock proteins using its disordered N-terminus. All core clock genes in Neurospora, as well as in higher eukaryotes, are predicted to be intrinsically disordered in some proportion and my labs seeks to identify the reason for the conservation of a high level of protein disorder in the circadian clock.