University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

Department of Biochemistry and Molecular Biotechnology

Publication Date

2021-10-30

Document Type

Article Preprint

Disciplines

Amino Acids, Peptides, and Proteins | Biochemistry | Enzymes and Coenzymes

Abstract

Ca2+/calmodulin dependent protein kinase II (CaMKII) is a signaling protein that is required for long-term memory formation. Ca2+/CaM activates CaMKII by binding to its regulatory segment, thereby freeing the substrate binding site. Despite having a large variety of interaction partners, the specificity of CaMKII interactions have not been structurally well-characterized. One exceptional feature of this kinase is that interaction with specific binding partners persistently activates CaMKII. To address the molecular details of this, we solved X-ray crystal structures of the CaMKII kinase domain bound to four different binding partners that modulate CaMKII activity in different ways. We show that all four partners bind in the same manner across the substrate binding site. We generated a sequence alignment based on our structural observations, which revealed conserved interactions. Using biochemistry and molecular dynamics simulations, we propose a mechanistic model that persistent CaMKII activity is facilitated by high affinity binding partners, which compete with the regulatory segment to allow substrate phosphorylation.

Keywords

Biochemistry, Ca2+/calmodulin dependent protein kinase II, long-term memory formation

Rights and Permissions

The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.

DOI of Published Version

10.1101/2020.10.25.354241

Source

bioRxiv 2020.10.25.354241; doi: https://doi.org/10.1101/2020.10.25.354241. Link to preprint on bioRxiv.

Comments

This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.

The PDF available for download is Version 3 of this preprint. The complete version history of this preprint is available at https://doi.org/10.1101/2020.10.25.354241.

Journal/Book/Conference Title

bioRxiv

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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