PROTEIN PHOSPHORYLATION AND DEGRADATION

The cycling of many clock components (e.g. KaiBC, FRQ, dPER, mPER1,2,3) is due to rhythmic transcription. Hand in hand with this though is the degradation of these proteins so that a constant level is never reached. This degradation occurs constantly throughout the cycle and is due to progressive phosphorylation that targets the protein for destruction by the ubiquitin-proteosome pathway (Green 1998, Harmer 2001).

In mammals, casein kinase I epsilon (CKIepsilon) phosphorylates mPER1 and mPER3. This results in rapid degradation of the proteins by the ubiquitin-proteosome pathway. Hence CKIepsilon controls mPER turnover in the mammalian circadian cycle. As the mPER proteins have an inhibitory effect on BMAL1 and mCLK, the actions of CKIepsilon have an indirect effect on the inhibition of these proteins by the mPER proteins. CKIepsilon has no effect on the action of the mCRY proteins on BMAL1 and mCLK (Akashi et al. 2002).

The role of phosphorylation in the regulation of the clock is supported by experiments that affect the phosphorylation of proteins. For example, frq mutants that have been altered to remove a phosphorylation site show a dramatic reduction in the rate of FRQ degradation, and an elongated period (over 30 hours). Inhibiting kinases has a similar effect (Liu et al 2000). On the other hand, mutations that increase the activity of CKIepsilon result in hyperphosphorylation of proteins and an increase protein degradation time. The result is a shortened period (Lowrey et al).

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