Molecular mechanism of activation-triggered subunit exchange in Ca2+/calmodulin-dependent protein kinase II

Bhattacharyya, Moitrayee; Stratton, Margaret M.; Going, Catherine C.; McSpadden, Ethan D.; Huang, Yongjian; Susa, Anna C.; Elleman, Anna V.; Cao, Yumeng; Pappireddi, Nishant; Burkhardt, Pawel; Gee, Christine L.; Barros, Tiago; Schulman, Howard; Williams, Evan R.; Kuriyan, John

doi:10.7554/elife.13405

Cited by 108 publications

(271 citation statements)

References 108 publications

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“…The vast majority of these masked particles classified as sixfold symmetric structures, with dimensions matching the crystallized dodecameric hub domain assembly212223 (Fig. 1g and Supplementary Fig.…”

Section: Resultsmentioning

confidence: 83%

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The CaMKII holoenzyme structure in activation-competent conformations

et al. 2017

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The Ca2+/calmodulin-dependent protein kinase II (CaMKII) assembles into large 12-meric holoenzymes, which is thought to enable regulatory processes required for synaptic plasticity underlying learning, memory and cognition. Here we used single particle electron microscopy (EM) to determine a pseudoatomic model of the CaMKIIα holoenzyme in an extended and activation-competent conformation. The holoenzyme is organized by a rigid central hub complex, while positioning of the kinase domains is highly flexible, revealing dynamic holoenzymes ranging from 15–35 nm in diameter. While most kinase domains are ordered independently, ∼20% appear to form dimers and <3% are consistent with a compact conformation. An additional level of plasticity is revealed by a small fraction of bona-fide 14-mers (<4%) that may enable subunit exchange. Biochemical and cellular FRET studies confirm that the extended state of CaMKIIα resolved by EM is the predominant form of the holoenzyme, even under molecular crowding conditions.

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Section: Resultsmentioning

confidence: 83%

“…22) residues 345–472) and monomeric human CaMKIIα kinase/regulatory domain (PDBID 2VZ6 (ref. 21) residues 13–300) into the EM density map by rigid body fitting using UCSF Chimera50.…”

Section: Methodsmentioning

confidence: 99%

The CaMKII holoenzyme structure in activation-competent conformations

et al. 2017

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“…rosetta has also emerged as model to reconstruct the ancestral functions of synaptic proteins like Homer, PSD-95 and CamKII [13 , 44,45]. The postsynaptic density protein Homer, which controls abundance and orientation of membrane receptors and regulates calcium signaling in neurons [46], unexpectedly localizes to the nucleus in S. rosetta (Figure 2j) [13 ].…”

Section: S Rosetta -A Colony-forming Choanoflagellate Enters the Stagementioning

confidence: 99%

Choanoflagellate models — Monosiga brevicollis and Salpingoeca rosetta

Hoffmeyer

Burkhardt

2016

Current Opinion in Genetics & Development

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Choanoflagellates are the closest single-celled relatives of animals and provide fascinating insights into developmental processes in animals. Two species, the choanoflagellates Monosiga brevicollis and Salpingoeca rosetta are emerging as promising model organisms to reveal the evolutionary origin of key animal innovations. In this review, we highlight how choanoflagellates are used to study the origin of multicellularity in animals. The newly available genomic resources and functional techniques provide important insights into the function of choanoflagellate pre- and postsynaptic proteins, cell-cell adhesion and signaling molecules and the evolution of animal filopodia and thus underscore the relevance of choanoflagellate models for evolutionary biology, neurobiology and cell biology research.

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“…At chemical synapses both CaM and the NMDA receptor subunit NR2B synergize to lock CaMKII in an active conformation conferring calcium-dependent plasticity (Bayer et al, 2001; Lisman et al, 2002; Bhattacharyya et al, 2016). A similar mechanism involving Cx36, CaM and CaMKII appears unlikely due to the overlapping binding site.…”

Section: Introductionmentioning

confidence: 99%

Structural and Functional Consequences of Connexin 36 (Cx36) Interaction with Calmodulin

Siu

Smirnova

Brown

et al. 2016

Front. Mol. Neurosci.

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Functional plasticity of neuronal gap junctions involves the interaction of the neuronal connexin36 with calcium/calmodulin-dependent kinase II (CaMKII). The important relationship between Cx36 and CaMKII must also be considered in the context of another protein partner, Ca2+ loaded calmodulin, binding an overlapping site in the carboxy-terminus of Cx36. We demonstrate that CaM and CaMKII binding to Cx36 is calcium-dependent, with Cx36 able to engage with CaM outside of the gap junction plaque. Furthermore, Ca2+ loaded calmodulin activates Cx36 channels, which is different to other connexins. The NMR solution structure demonstrates that CaM binds Cx36 in its characteristic compact state with major hydrophobic contributions arising from W277 at anchor position 1 and V284 at position 8 of Cx36. Our results establish Cx36 as a hub binding Ca2+ loaded CaM and they identify this interaction as a critical step with implications for functions preceding the initiation of CaMKII mediated plasticity at electrical synapses.

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Molecular mechanism of activation-triggered subunit exchange in Ca2+/calmodulin-dependent protein kinase II

Cited by 108 publications

References 108 publications

The CaMKII holoenzyme structure in activation-competent conformations

The CaMKII holoenzyme structure in activation-competent conformations

Choanoflagellate models — Monosiga brevicollis and Salpingoeca rosetta

Structural and Functional Consequences of Connexin 36 (Cx36) Interaction with Calmodulin

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