8D7N

Human Casein kinase 1 delta in complex with phosphorylated human PERIOD2 FASP peptide

8D7N の概要

• エントリーDOI: 10.2210/pdb8d7n/pdb
• 分子名称: Casein kinase I isoform delta, Period circadian protein homolog 2 peptide (3 entities in total)
• 機能のキーワード: transferase, circadian clock protein, period2, kinase, complex, transferase-circadian clock protein complex, transferase/circadian clock protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 72745.10

構造登録者

Philpott, J.M.,Freeberg, A.M.,Tripathi, S.M.,Partch, C.L. (登録日: 2022-06-07, 公開日: 2023-05-17, 最終更新日: 2023-10-25)

主引用文献

Philpott, J.M.,Freeberg, A.M.,Park, J.,Lee, K.,Ricci, C.G.,Hunt, S.R.,Narasimamurthy, R.,Segal, D.H.,Robles, R.,Cai, Y.,Tripathi, S.,McCammon, J.A.,Virshup, D.M.,Chiu, J.C.,Lee, C.,Partch, C.L.
PERIOD phosphorylation leads to feedback inhibition of CK1 activity to control circadian period.
Mol.Cell, 83:1677-1692.e8, 2023

PubMed Abstract: PERIOD (PER) and Casein Kinase 1δ regulate circadian rhythms through a phosphoswitch that controls PER stability and repressive activity in the molecular clock. CK1δ phosphorylation of the familial advanced sleep phase (FASP) serine cluster embedded within the Casein Kinase 1 binding domain (CK1BD) of mammalian PER1/2 inhibits its activity on phosphodegrons to stabilize PER and extend circadian period. Here, we show that the phosphorylated FASP region (pFASP) of PER2 directly interacts with and inhibits CK1δ. Co-crystal structures in conjunction with molecular dynamics simulations reveal how pFASP phosphoserines dock into conserved anion binding sites near the active site of CK1δ. Limiting phosphorylation of the FASP serine cluster reduces product inhibition, decreasing PER2 stability and shortening circadian period in human cells. We found that Drosophila PER also regulates CK1δ via feedback inhibition through the phosphorylated PER-Short domain, revealing a conserved mechanism by which PER phosphorylation near the CK1BD regulates CK1 kinase activity.

PubMed: 37207626
DOI: 10.1016/j.molcel.2023.04.019

実験手法

X-RAY DIFFRACTION (1.66 Å)