Positional Syntenic Cloning and Functional Characterization of the Mammalian Circadian Mutation tau
摘要：
The tau mutation is a semidominant autosomal allele that dramatically shortens period length of circadian rhythms in Syrian hamsters. We report the molecular identification of the tau locus using genetically directed representational difference analysis to define a region of conserved synteny in hamsters with both the mouse and human genomes. The tau locus is encoded by casein kinase I epsilon (CKIε), a homolog of the Drosophila circadian gene double-time. In vitro expression and functional studies of wild-type and tau mutant CKIε enzyme reveal that the mutant enzyme has a markedly reduced maximal velocity and autophosphorylation state. In addition, in vitro CKIε can interact with mammalian PERIOD proteins, and the mutant enzyme is deficient in its ability to phosphorylate PERIOD. We conclude that tau is an allele of hamster CKIε and propose a mechanism by which the mutation leads to the observed aberrant circadian phenotype in mutant animals.
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关键词：
Proteins Evolution, Molecular Sequence Analysis, Protein Protein Structure, Tertiary Protein Folding Sequence Homology, Amino Acid Protein Stability Models, Molecular Databases, Protein
DOI：
10.1371/journal.pcbi.1003291
被引量：
年份：
2000
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