Diernfellner Axel C R, Querfurth Christina, Salazar Carlos, Höfer Thomas, Brunner Michael
University of Heidelberg Biochemistry Center, 69120 Heidelberg, Germany.
Genes Dev. 2009 Sep 15;23(18):2192-200. doi: 10.1101/gad.538209.
The Neurospora clock protein FREQUENCY (FRQ) is an essential regulator of the circadian transcription factor WHITE COLLAR COMPLEX (WCC). In the course of a circadian period, the subcellular distribution of FRQ shifts from mainly nuclear to mainly cytosolic. This shift is crucial for coordinating the negative and positive limbs of the clock. We show that the subcellular redistribution of FRQ on a circadian time scale is governed by rapid, noncircadian cycles of nuclear import and export. The rate of nuclear import of newly synthesized FRQ is progressively reduced in a phosphorylation-dependent manner, leading to an increase in the steady-state level of cytoplasmic FRQ. The long-period frq(7) mutant displays reduced kinetics of FRQ(7) protein phosphorylation and a prolonged accumulation in the nucleus. We present a mathematical model that describes the cytoplasmic accumulation of wild-type and mutant FRQ on a circadian time scale on the basis of frequency-modulated rapid nucleocytoplasmic shuttling cycles.
粗糙脉孢菌生物钟蛋白频率（FRQ）是昼夜节律转录因子白领复合体（WCC）的重要调节因子。在一个昼夜节律周期中，FRQ的亚细胞分布从主要在细胞核转变为主要在细胞质。这种转变对于协调生物钟的负向和正向环节至关重要。我们发现，FRQ在昼夜时间尺度上的亚细胞重新分布受快速、非昼夜节律的核输入和输出循环调控。新合成的FRQ的核输入速率以磷酸化依赖的方式逐渐降低，导致细胞质中FRQ的稳态水平增加。长周期frq(7)突变体表现出FRQ(7)蛋白磷酸化动力学降低以及在细胞核中积累时间延长。我们提出了一个数学模型，该模型基于频率调制的快速核质穿梭循环，描述了野生型和突变型FRQ在昼夜时间尺度上的细胞质积累情况。
