CaMKII binds both substrates and activators at the active site [preprint]
Esposito, Edward A.
Kelch, Brian A
Garman, Scott C.
Stratton, Margaret M.
UMass Chan AffiliationsBiochemistry and Molecular Biotechnology
Ca2+/calmodulin dependent protein kinase II
long-term memory formation
Amino Acids, Peptides, and Proteins
Enzymes and Coenzymes
MetadataShow full item record
AbstractCa2+/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.
bioRxiv 2020.10.25.354241; doi: https://doi.org/10.1101/2020.10.25.354241. Link to preprint on bioRxiv.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/29888
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 Preprints are preliminary reports of work that have not been certified by peer review.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.