Department of Biochemistry and Molecular Biotechnology
Amino Acids, Peptides, and Proteins | Biochemistry | Enzymes and Coenzymes
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.
Biochemistry, Ca2+/calmodulin dependent protein kinase II, long-term memory formation
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DOI of Published Version
bioRxiv 2020.10.25.354241; doi: https://doi.org/10.1101/2020.10.25.354241. Link to preprint on bioRxiv.
Ozden C, Sloutsky R, Mitsugi T, Santos N, Agnello E, Gaubitz C, Foster J, Lapinskas E, Esposito EA, Saneyoshi T, Kelch BA, Garman SC, Hayashi Y, Stratton MM. (2021). CaMKII binds both substrates and activators at the active site [preprint]. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1101/2020.10.25.354241. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/2094
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