PMID- 29784789
OWN - NLM
STAT- MEDLINE
DCOM- 20180904
LR  - 20211204
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 115
IP  - 23
DP  - 2018 Jun 5
TI  - CK1delta/epsilon protein kinase primes the PER2 circadian phosphoswitch.
PG  - 5986-5991
LID - 10.1073/pnas.1721076115 [doi]
AB  - Multisite phosphorylation of the PERIOD 2 (PER2) protein is the key step that 
      determines the period of the mammalian circadian clock. Previous studies 
      concluded that an unidentified kinase is required to prime PER2 for subsequent 
      phosphorylation by casein kinase 1 (CK1), an essential clock component that is 
      conserved from algae to humans. These subsequent phosphorylations stabilize PER2, 
      delay its degradation, and lengthen the period of the circadian clock. Here, we 
      perform a comprehensive biochemical and biophysical analysis of mouse PER2 
      (mPER2) priming phosphorylation and demonstrate, surprisingly, that CK1delta/epsilon is 
      indeed the priming kinase. We find that both CK1epsilon and a recently characterized 
      CK1delta2 splice variant more efficiently prime mPER2 for downstream phosphorylation 
      in cells than the well-studied splice variant CK1delta1. While CK1 phosphorylation of 
      PER2 was previously shown to be robust to changes in the cellular environment, 
      our phosphoswitch mathematical model of circadian rhythms shows that the CK1 
      carboxyl-terminal tail can allow the period of the clock to be sensitive to 
      cellular signaling. These studies implicate the extreme carboxyl terminus of CK1 
      as a key regulator of circadian timing.
CI  - Copyright (c) 2018 the Author(s). Published by PNAS.
FAU - Narasimamurthy, Rajesh
AU  - Narasimamurthy R
AD  - Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 169857 
      Singapore.
FAU - Hunt, Sabrina R
AU  - Hunt SR
AD  - Department of Chemistry and Biochemistry, University of California, Santa Cruz, 
      CA 95064.
FAU - Lu, Yining
AU  - Lu Y
AD  - Department of Mathematics, University of Michigan, Ann Arbor, MI 48109.
AD  - Department of Computational Medicine and Bioinformatics, University of Michigan, 
      Ann Arbor, MI 48109.
FAU - Fustin, Jean-Michel
AU  - Fustin JM
AD  - Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto 
      University, Sakyo-ku, 606-8501 Kyoto, Japan.
FAU - Okamura, Hitoshi
AU  - Okamura H
AD  - Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto 
      University, Sakyo-ku, 606-8501 Kyoto, Japan.
FAU - Partch, Carrie L
AU  - Partch CL
AD  - Department of Chemistry and Biochemistry, University of California, Santa Cruz, 
      CA 95064.
AD  - Center for Circadian Biology, University of California, San Diego, La Jolla, CA 
      92093.
FAU - Forger, Daniel B
AU  - Forger DB
AD  - Department of Mathematics, University of Michigan, Ann Arbor, MI 48109.
AD  - Department of Computational Medicine and Bioinformatics, University of Michigan, 
      Ann Arbor, MI 48109.
AD  - The Michigan Institute for Data Science, University of Michigan, Ann Arbor, MI 
      48109.
FAU - Kim, Jae Kyoung
AU  - Kim JK
AUID- ORCID: 0000-0001-7842-2172
AD  - Department of Mathematical Sciences, Korea Advanced Institute of Science and 
      Technology, 34141 Daejeon, Korea.
FAU - Virshup, David M
AU  - Virshup DM
AUID- ORCID: 0000-0001-6976-850X
AD  - Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 169857 
      Singapore; david.virshup@duke-nus.edu.sg.
AD  - Department of Pediatrics, Duke University Medical Center, Durham, NC 27710.
LA  - eng
GR  - R01 GM107069/GM/NIGMS NIH HHS/United States
GR  - R01 GM121507/GM/NIGMS NIH HHS/United States
GR  - S10 OD018455/OD/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20180521
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (PER2 protein, human)
RN  - 0 (Per2 protein, mouse)
RN  - 0 (Period Circadian Proteins)
RN  - EC 2.7.11.1 (Casein Kinase 1 epsilon)
RN  - EC 2.7.11.1 (Casein Kinase Idelta)
SB  - IM
CIN - doi: 10.1073/pnas.1721371115
MH  - Animals
MH  - Casein Kinase 1 epsilon/*metabolism
MH  - Casein Kinase Idelta/*metabolism
MH  - Circadian Rhythm/*physiology
MH  - HEK293 Cells
MH  - Humans
MH  - Mice
MH  - Period Circadian Proteins/genetics/*metabolism
MH  - Phosphorylation
PMC - PMC6003379
OTO - NOTNLM
OT  - cell regulation
OT  - circadian rhythms
OT  - protein kinase
COIS- The authors declare no conflict of interest.
EDAT- 2018/05/23 06:00
MHDA- 2018/09/05 06:00
PMCR- 2018/05/21
CRDT- 2018/05/23 06:00
PHST- 2018/05/23 06:00 [pubmed]
PHST- 2018/09/05 06:00 [medline]
PHST- 2018/05/23 06:00 [entrez]
PHST- 2018/05/21 00:00 [pmc-release]
AID - 1721076115 [pii]
AID - 201721076 [pii]
AID - 10.1073/pnas.1721076115 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2018 Jun 5;115(23):5986-5991. doi: 
      10.1073/pnas.1721076115. Epub 2018 May 21.