Differential effects of PER2 phosphorylation: molecular basis for the human familial advanced sleep phase syndrome (FASPS)

摘要: PERIOD (PER) proteins are central components within the mammalian circadian oscillator, and believed to form a negative feedback complex that inhibits their own transcription at particular phase. Phosphorylation of PER regulates stability as well subcellular localization. In systematic screen, we have identified 21 phosphorylated residues mPER2 including Ser 659, which is mutated in patients suffering from familial advanced sleep phase syndrome (FASPS). When expressing FASPS-mutated oscillating fibroblasts, can phenocopy short period FASPS patients’ behavior. We show phosphorylation 659 results nuclear retention stabilization mPER2, whereas other sites leads degradation. To conceptualize our findings, use mathematical modeling predict differential events result opposite phenotypes. Indeed, interference with specific aspects either or long periods fibroblasts. This concept explains not only phenotype, but also effect tau mutation hamster doubletime mutants (dbt S dbt L )i nDrosophila.