Dataset Information

Developmental stage-dependent regulation of spine formation by calcium-calmodulin-dependent protein kinase II? and Rap1.

ABSTRACT: The roles of calcium-calmodulin-dependent protein kinase II-alpha (CaMKII?) in the expression of long-term synaptic plasticity in the adult brain have been extensively studied. However, how increased CaMKII? activity controls the maturation of neuronal circuits remains incompletely understood. Herein, we show that pyramidal neurons without CaMKII? activity upregulate the rate of spine addition, resulting in elevated spine density. Genetic elimination of CaMKII? activity specifically eliminated the observed maturation-dependent suppression of spine formation. Enhanced spine formation was associated with the stabilization of actin in the spine and could be reversed by increasing the activity of the small GTPase Rap1. CaMKII? activity was critical in the phosphorylation of synaptic Ras GTPase-activating protein (synGAP), the dispersion of synGAP from postsynaptic sites, and the activation of postsynaptic Rap1. CaMKII? is already known to be essential in learning and memory, but our findings suggest that CaMKII? plays an important activity-dependent role in restricting spine density during postnatal development.

SUBMITTER: Cornelia Koeberle S

PROVIDER: S-EPMC5645322 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Developmental stage-dependent regulation of spine formation by calcium-calmodulin-dependent protein kinase IIα and Rap1.

Cornelia Koeberle Solveigh S Tanaka Shinji S Kuriu Toshihiko T Iwasaki Hirohide H Koeberle Andreas A Koeberle Andreas A Schulz Alexander A Helbing Dario-Lucas DL Yamagata Yoko Y Morrison Helen H Okabe Shigeo S

Scientific reports 20171017 1

The roles of calcium-calmodulin-dependent protein kinase II-alpha (CaMKIIα) in the expression of long-term synaptic plasticity in the adult brain have been extensively studied. However, how increased CaMKIIα activity controls the maturation of neuronal circuits remains incompletely understood. Herein, we show that pyramidal neurons without CaMKIIα activity upregulate the rate of spine addition, resulting in elevated spine density. Genetic elimination of CaMKIIα activity specifically eliminated t ...[more]

PMID: 29042611

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Project description: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.

Dataset Information

Developmental stage-dependent regulation of spine formation by calcium-calmodulin-dependent protein kinase II? and Rap1.

Publications

Developmental stage-dependent regulation of spine formation by calcium-calmodulin-dependent protein kinase IIα and Rap1.

Similar Datasets

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