Differential effects of PER2 phosphorylation: molecular basis for the human familial advanced sleep phase syndrome (FASPS)
Differential effects of PER2 phosphorylation: molecular basis for the human familial advanced sleep phase syndrome (FASPS)
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DOI：
10.1101/gad.397006
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发表时间：
2006-10-01
影响因子：
10.5
通讯作者：
Kramer, Achim
中科院分区：
文献类型：
--
作者：
Vanselow, Katja;Vanselow, Jens T.;Kramer, Achim
PERIOD（PER）蛋白是哺乳动物昼夜节律振荡器内的中心组分，并且被认为形成负反馈复合物，其在特定的昼夜节律相位抑制其自身的转录。PER蛋白的磷酸化调节其稳定性以及其亚细胞定位。在一个系统的筛选中，我们已经确定了21个磷酸化残基的mPER 2，包括Ser 659，这是突变的患者患有家族性晚期睡眠综合征（FASPS）。当在振荡成纤维细胞中表达FASPS突变的mPER 2时，我们可以对FASPS患者行为的短期和晚期进行表型复制。我们发现，在丝氨酸659磷酸化的结果在核保留和稳定的mPER2，而在其他网站的磷酸化导致mPER2降解。为了使我们的发现概念化，我们使用数学建模并预测差异PER磷酸化事件可导致相反时期的表型。事实上，干扰mPER 2磷酸化的特定方面导致振荡成纤维细胞中的短或长时间。这一概念不仅解释了FASPS表型，而且还解释了仓鼠中tau突变以及果蝇中双倍时间突变体（dbtS和dbtL）的影响。
PERIOD (PER) proteins are central components within the mammalian circadian oscillator, and are believed to form a negative feedback complex that inhibits their own transcription at a particular circadian phase. Phosphorylation of PER proteins regulates their stability as well as their subcellular localization. In a systematic screen, we have identified 21 phosphorylated residues of mPER2 including Ser 659, which is mutated in patients suffering from familial advanced sleep phase syndrome (FASPS). When expressing FASPS-mutated mPER2 in oscillating fibroblasts, we can phenocopy the short period and advanced phase of FASPS patients' behavior. We show that phosphorylation at Ser 659 results in nuclear retention and stabilization of mPER2, whereas phosphorylation at other sites leads to mPER2 degradation. To conceptualize our findings, we use mathematical modeling and predict that differential PER phosphorylation events can result in opposite period phenotypes. Indeed, interference with specific aspects of mPER2 phosphorylation leads to either short or long periods in oscillating fibroblasts. This concept explains not only the FASPS phenotype, but also the effect of the tau mutation in hamster as well as the doubletime mutants (dbtS and dbtL) in Drosophila.