每2
生物钟
昼夜节律
生物
细胞生物学
生物物理学
神经科学
时钟
作者
Najumuddin,Muhammad Fakhar,Mehreen Gul,Sajid Rashid
标识
DOI:10.1016/j.abb.2018.05.020
摘要
Circadian rhythm is rhythmic gene expression that is involved in various processes of life over a day and night cycle. The rhythmic sleep disorders arise due to misalignment of sleep-wake cycle influenced by phosphorylation of PERIOD2 (PER2) phosphodegron (SSGYGS), the conserved interaction site of β-transducin repeat-containing protein (βTrCP1). Here, we employed in silico approach to study the interaction pattern of βTrCP1 with PER2WT, PER2SER480ALA and PER2SER484ALA phosphodegron peptides. Substitution of phosphorylatable SER480 or SER484 into ALA resulted in the shifting of PER2 phosphodegron binding at the lower face of β-propeller, by involvement of both SER residues. PER2 binding at the shallow cavity of βTrCP1 induced conformational readjustment in ARG524 residue that connected the upper hemisphere base (10.5 Å) with the roof of lower hemisphere (6.6 Å) to create a uniform tunnel-like structure. In the absence of phosphorylation, PER2 and βTrCP1 binding stability may be compromised resulting in the enhancement of PER2 level in the cytoplasm that may disrupt circadian clock and aging. Taken together, this study will help in understanding the structural basis of conserved phosphoswitch mechanism in the mammalian circadian oscillation.
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