8d7o

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

spinqualitylabelsall models 8d7o, resolution 1.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8d7o is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.65Å Ligands: SEP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease KC1D_HUMAN Familial advanced sleep-phase syndrome. The disease is caused by mutations affecting the gene represented in this entry. Function KC1D_HUMAN Essential serine/threonine-protein kinase that regulates diverse cellular growth and survival processes including Wnt signaling, DNA repair and circadian rhythms. It can phosphorylate a large number of proteins. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. Phosphorylates connexin-43/GJA1, MAP1A, SNAPIN, MAPT/TAU, TOP2A, DCK, HIF1A, EIF6, p53/TP53, DVL2, DVL3, ESR1, AIB1/NCOA3, DNMT1, PKD2, YAP1, PER1 and PER2. Central component of the circadian clock. May act as a negative regulator of circadian rhythmicity by phosphorylating PER1 and PER2, leading to retain PER1 in the cytoplasm. YAP1 phosphorylation promotes its SCF(beta-TRCP) E3 ubiquitin ligase-mediated ubiquitination and subsequent degradation. DNMT1 phosphorylation reduces its DNA-binding activity. Phosphorylation of ESR1 and AIB1/NCOA3 stimulates their activity and coactivation. Phosphorylation of DVL2 and DVL3 regulates WNT3A signaling pathway that controls neurite outgrowth. EIF6 phosphorylation promotes its nuclear export. Triggers down-regulation of dopamine receptors in the forebrain. Activates DCK in vitro by phosphorylation. TOP2A phosphorylation favors DNA cleavable complex formation. May regulate the formation of the mitotic spindle apparatus in extravillous trophoblast. Modulates connexin-43/GJA1 gap junction assembly by phosphorylation. Probably involved in lymphocyte physiology. Regulates fast synaptic transmission mediated by glutamate. Publication Abstract from PubMed PERIOD (PER) and Casein Kinase 1delta regulate circadian rhythms through a phosphoswitch that controls PER stability and repressive activity in the molecular clock. CK1delta 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 CK1delta. Co-crystal structures in conjunction with molecular dynamics simulations reveal how pFASP phosphoserines dock into conserved anion binding sites near the active site of CK1delta. 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 CK1delta via feedback inhibition through the phosphorylated PER-Short domain, revealing a conserved mechanism by which PER phosphorylation near the CK1BD regulates CK1 kinase activity. PERIOD phosphorylation leads to feedback inhibition of CK1 activity to control circadian period.,Philpott JM, Freeberg AM, Park J, Lee K, Ricci CG, Hunt SR, Narasimamurthy R, Segal DH, Robles R, Cai Y, Tripathi S, McCammon JA, Virshup DM, Chiu JC, Lee C, Partch CL Mol Cell. 2023 May 18;83(10):1677-1692.e8. doi: 10.1016/j.molcel.2023.04.019. PMID:37207626 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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