PMID- 30072381
OWN - NLM
STAT- MEDLINE
DCOM- 20190405
LR  - 20210205
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 293
IP  - 38
DP  - 2018 Sep 21
TI  - The Ras-like GTPase Rem2 is a potent inhibitor of calcium/calmodulin-dependent 
      kinase II activity.
PG  - 14798-14811
LID - 10.1074/jbc.RA118.003560 [doi]
AB  - Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a well-characterized, 
      abundant protein kinase that regulates a diverse set of functions in a 
      tissue-specific manner. For example, in heart muscle, CaMKII regulates Ca(2+) 
      homeostasis, whereas in neurons, CaMKII regulates activity-dependent dendritic 
      remodeling and long-term potentiation (LTP), a neurobiological correlate of 
      learning and memory. Previously, we identified the GTPase Rem2 as a critical 
      regulator of dendrite branching and homeostatic plasticity in the vertebrate 
      nervous system. Here, we report that Rem2 directly interacts with CaMKII and 
      potently inhibits the activity of the intact holoenzyme, a previously unknown 
      Rem2 function. Our results suggest that Rem2 inhibition involves interaction with 
      both the CaMKII hub domain and substrate recognition domain. Moreover, we found 
      that Rem2-mediated inhibition of CaMKII regulates dendritic branching in cultured 
      hippocampal neurons. Lastly, we report that substitution of two key amino acid 
      residues in the Rem2 N terminus (Arg-79 and Arg-80) completely abolishes its 
      ability to inhibit CaMKII. We propose that our biochemical findings will enable 
      further studies unraveling the functional significance of Rem2 inhibition of 
      CaMKII in cells.
CI  - (c) 2018 Royer et al.
FAU - Royer, Leandro
AU  - Royer L
AD  - From the Department of Biology.
FAU - Herzog, Josiah J
AU  - Herzog JJ
AD  - From the Department of Biology.
FAU - Kenny, Katelyn
AU  - Kenny K
AD  - From the Department of Biology.
FAU - Tzvetkova, Boriana
AU  - Tzvetkova B
AD  - From the Department of Biology.
FAU - Cochrane, Jesse C
AU  - Cochrane JC
AD  - Department of Molecular Biology and Genetics, Massachusetts General Hospital and 
      Harvard Medical School, Boston, Massachusetts 02114.
FAU - Marr, Michael T 2nd
AU  - Marr MT 2nd
AD  - From the Department of Biology, mmarr@brandeis.edu.
AD  - Rosenstiel Basic Medical Sciences Research Center.
FAU - Paradis, Suzanne
AU  - Paradis S
AD  - From the Department of Biology, paradis@brandeis.edu.
AD  - Volen Center for Complex Systems, and.
AD  - National Center for Behavioral Genomics, Brandeis University, Waltham, 
      Massachusetts 02454 and.
LA  - eng
GR  - R01 GM117034/GM/NIGMS NIH HHS/United States
GR  - R01 NS065856/NS/NINDS NIH HHS/United States
GR  - R21 NS102661/NS/NINDS NIH HHS/United States
GR  - T32 EB009419/EB/NIBIB NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20180802
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)
RN  - EC 3.6.5.2 (Monomeric GTP-Binding Proteins)
RN  - EC 3.6.5.2 (REM2 protein, human)
RN  - EC 3.6.5.2 (Rem2 protein, mouse)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Calcium/metabolism
MH  - Calcium-Calmodulin-Dependent Protein Kinase Type 2/*antagonists & inhibitors
MH  - Cells, Cultured
MH  - HEK293 Cells
MH  - Hippocampus/cytology/enzymology/metabolism
MH  - Homeostasis
MH  - Humans
MH  - Learning
MH  - Long-Term Potentiation
MH  - Memory
MH  - Mice
MH  - Monomeric GTP-Binding Proteins/chemistry/*physiology
MH  - Neuronal Plasticity
MH  - Neurons/metabolism
MH  - Phosphorylation
MH  - Substrate Specificity
PMC - PMC6153278
OTO - NOTNLM
OT  - Ca2+/calmodulin-dependent protein kinase II (CaMKII)
OT  - GTPase
OT  - RGK family
OT  - Rem2
OT  - autophosphorylation
OT  - calcium
OT  - inhibitor
OT  - phosphorylation
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article
EDAT- 2018/08/04 06:00
MHDA- 2019/04/06 06:00
PMCR- 2019/09/21
CRDT- 2018/08/04 06:00
PHST- 2018/04/26 00:00 [received]
PHST- 2018/07/20 00:00 [revised]
PHST- 2018/08/04 06:00 [pubmed]
PHST- 2019/04/06 06:00 [medline]
PHST- 2018/08/04 06:00 [entrez]
PHST- 2019/09/21 00:00 [pmc-release]
AID - S0021-9258(20)30875-9 [pii]
AID - RA118.003560 [pii]
AID - 10.1074/jbc.RA118.003560 [doi]
PST - ppublish
SO  - J Biol Chem. 2018 Sep 21;293(38):14798-14811. doi: 10.1074/jbc.RA118.003560. Epub 
      2018 Aug 2.