NUCLEAR TRANSLOCATION

A key step in all eukaryotic circadian clock mechanisms is the translocation of a protein or proteins from the cytoplasm into the nucleus. These proteins are always components of the negative arm of the cycle, as the positive elements are always nuclear proteins (Harmer 2001). The regulated entry of the proteins dPER and dTIM play an important part in the Drosophila biological clock. 

Both dPER and dTIM contain certain motifs and sequences. In addition to a PAS domain, both also possess a nuclear localisation signal and a cytoplasmic localisation domain (CLD). These CLDs keep the proteins localised in the cytoplasm. In dPER, the CLD forms a binding site for dTIM. This means that when dPER and dTIM heterodimerise, the CLD region of dTIM and dPER are blocked. This allows the two proteins to be translocated into the nucleus (Saez and Young, 1996). It appears that dTIM is only needed for the translocation of dPER, and the conversion of the dPER/ dTIM heterodimers to nuclear dPER is a necessary step required to complete the repression of dclk and cyc to prevent the transcription of dper and dtim (Rothenflüh 2000). 

In many cases the mechanism by which negative elements are localised to the nucleus is unclear. For example in mammalian clocks, the co-expression of the mCRY and mPER proteins leads to efficient nuclear localisation. However mPER 1 and mPER2 can still enter the nucleus without mCRY (as seen in mcry deficient mice). It is thought that the localisation of mPER1 and mPER2 depends on a number of factors including the mCRY proteins, other proteins (such as casein kinase I Epsilon (which phosphorylates mPER, keeping mPER1 in the cytoplasm)), and the phosphorylation states of both mPER and other proteins (Shearman 2000).

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