Interactive structural analysis of βTrCP1 and PER2 phosphoswitch binding through dynamics simulation assay.

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 PER2^WT, PER2^SER480ALA and PER2^SER484ALA 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.

KEYWORDS: {{ getKeywords(articleDetailText.words) }}