PMID- 31150387
OWN - NLM
STAT- MEDLINE
DCOM- 20191115
LR  - 20201214
IS  - 1553-7358 (Electronic)
IS  - 1553-734X (Print)
IS  - 1553-734X (Linking)
VI  - 15
IP  - 5
DP  - 2019 May
TI  - Conformational coupling by trans-phosphorylation in calcium calmodulin dependent 
      kinase II.
PG  - e1006796
LID - 10.1371/journal.pcbi.1006796 [doi]
LID - e1006796
AB  - The calcium calmodulin-dependent protein kinase II (CaMKII) is a dodecameric 
      holoenzyme important for encoding memory. Its activation, triggered by binding of 
      calcium-calmodulin, persists autonomously after calmodulin dissociation. One 
      (receiver) kinase captures and subsequently phosphorylates the regulatory domain 
      peptide of a donor kinase forming a chained dimer as the first stage of 
      autonomous activation. Protein dynamics simulations examined the conformational 
      changes triggered by dimer formation and phosphorylation, aimed to provide a 
      molecular rationale for human mutations that result in learning disabilities. 
      Ensembles generated from X-ray crystal structures were characterized by network 
      centrality and community analysis. Mutual information related collective motions 
      to local fragment dynamics encoded with a structural alphabet. Implicit solvent 
      tCONCOORD conformational ensembles revealed the dynamic architecture of inactive 
      kinase domains was co-opted in the activated dimer but the network hub shifted 
      from the nucleotide binding cleft to the captured peptide. Explicit solvent 
      molecular dynamics (MD) showed nucleotide and substrate binding determinants 
      formed coupled nodes in long-range signal relays between regulatory peptides in 
      the dimer. Strain in the extended captured peptide was balanced by reduced 
      flexibility of the receiver kinase C-lobe core. The relays were organized around 
      a hydrophobic patch between the captured peptide and a key binding helix. The 
      human mutations aligned along the relays. Thus, these mutations could disrupt the 
      allosteric network alternatively, or in addition, to altered binding affinities. 
      Non-binding protein sectors distant from the binding sites mediated the 
      allosteric signalling; providing possible targets for inhibitor design. 
      Phosphorylation of the peptide modulated the dielectric of its binding pocket to 
      strengthen the patch, non-binding sectors, domain interface and temporal 
      correlations between parallel relays. These results provide the molecular details 
      underlying the reported positive kinase cooperativity to enrich the discussion on 
      how autonomous activation by phosphorylation leads to long-term behavioural 
      effects.
FAU - Pandini, Alessandro
AU  - Pandini A
AUID- ORCID: 0000-0002-4158-233X
AD  - Department of Computer Science-Synthetic Biology Theme, Brunel University London, 
      Uxbridge, United Kingdom.
AD  - The Thomas Young Centre for Theory and Simulation of Materials, London, United 
      Kingdom.
AD  - Computational Cell and Molecular Biology, the Francis Crick Institute, London, 
      United Kingdom.
FAU - Schulman, Howard
AU  - Schulman H
AUID- ORCID: 0000-0002-0353-2315
AD  - Allosteros Therapeutics Inc., Sunnyvale, CA, United States of America.
FAU - Khan, Shahid
AU  - Khan S
AUID- ORCID: 0000-0002-0361-6068
AD  - Computational Cell and Molecular Biology, the Francis Crick Institute, London, 
      United Kingdom.
AD  - Molecular Biology Consortium, Lawrence Berkeley National Laboratory, Berkeley, 
      CA, United States of America.
LA  - eng
GR  - R01 GM101277/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190531
PL  - United States
TA  - PLoS Comput Biol
JT  - PLoS computational biology
JID - 101238922
RN  - 0 (Calmodulin)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Binding Sites
MH  - Calcium/metabolism
MH  - Calcium-Calmodulin-Dependent Protein Kinase Type 2/*metabolism/*ultrastructure
MH  - Calmodulin/metabolism
MH  - Humans
MH  - Molecular Dynamics Simulation
MH  - Phosphorylation/physiology
MH  - Protein Binding
MH  - Protein Conformation
MH  - Signal Transduction
PMC - PMC6576796
COIS- HS is a paid employee of Allosteros Therapeutics.
EDAT- 2019/06/01 06:00
MHDA- 2019/11/16 06:00
PMCR- 2019/05/31
CRDT- 2019/06/01 06:00
PHST- 2019/01/16 00:00 [received]
PHST- 2019/03/28 00:00 [accepted]
PHST- 2019/06/17 00:00 [revised]
PHST- 2019/06/01 06:00 [pubmed]
PHST- 2019/11/16 06:00 [medline]
PHST- 2019/06/01 06:00 [entrez]
PHST- 2019/05/31 00:00 [pmc-release]
AID - PCOMPBIOL-D-19-00018 [pii]
AID - 10.1371/journal.pcbi.1006796 [doi]
PST - epublish
SO  - PLoS Comput Biol. 2019 May 31;15(5):e1006796. doi: 10.1371/journal.pcbi.1006796. 
      eCollection 2019 May.