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CaMKII binds both substrates and activators at the active site. 2022

Can Özden, and Roman Sloutsky, and Tomohiro Mitsugi, and Nicholas Santos, and Emily Agnello, and Christl Gaubitz, and Joshua Foster, and Emily Lapinskas, and Edward A Esposito, and Takeo Saneyoshi, and Brian A Kelch, and Scott C Garman, and Yasunori Hayashi, and Margaret M Stratton
Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, MA 01003, USA; Molecular and Cellular Biology Graduate Program, University of Massachusetts, Amherst, MA 01003, USA.

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a signaling protein required for long-term memory. When activated by Ca2+/CaM, it sustains activity even after the Ca2+ dissipates. In addition to the well-known autophosphorylation-mediated mechanism, interaction with specific binding partners also persistently activates CaMKII. A long-standing model invokes two distinct S and T sites. If an interactor binds at the T-site, then it will preclude autoinhibition and allow substrates to be phosphorylated at the S site. Here, we specifically test this model with X-ray crystallography, molecular dynamics simulations, and biochemistry. Our data are inconsistent with this model. Co-crystal structures of four different activators or substrates show that they all bind to a single continuous site across the kinase domain. We propose a mechanistic model where persistent CaMKII activity is facilitated by high-affinity binding partners that kinetically compete with autoinhibition by the regulatory segment to allow substrate phosphorylation.

UI MeSH Term Description Entries
D010766 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Phosphorylations
D011499 Protein Processing, Post-Translational Any of various enzymatically catalyzed post-translational modifications of PEPTIDES or PROTEINS in the cell of origin. These modifications include carboxylation; HYDROXYLATION; ACETYLATION; PHOSPHORYLATION; METHYLATION; GLYCOSYLATION; ubiquitination; oxidation; proteolysis; and crosslinking and result in changes in molecular weight and electrophoretic motility. Amino Acid Modification, Post-Translational,Post-Translational Modification,Post-Translational Protein Modification,Posttranslational Modification,Protein Modification, Post-Translational,Amino Acid Modification, Posttranslational,Post-Translational Amino Acid Modification,Post-Translational Modifications,Post-Translational Protein Processing,Posttranslational Amino Acid Modification,Posttranslational Modifications,Posttranslational Protein Processing,Protein Processing, Post Translational,Protein Processing, Posttranslational,Amino Acid Modification, Post Translational,Modification, Post-Translational,Modification, Post-Translational Protein,Modification, Posttranslational,Modifications, Post-Translational,Modifications, Post-Translational Protein,Modifications, Posttranslational,Post Translational Amino Acid Modification,Post Translational Modification,Post Translational Modifications,Post Translational Protein Modification,Post Translational Protein Processing,Post-Translational Protein Modifications,Processing, Post-Translational Protein,Processing, Posttranslational Protein,Protein Modification, Post Translational,Protein Modifications, Post-Translational
D002118 Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Coagulation Factor IV,Factor IV,Blood Coagulation Factor IV,Calcium-40,Calcium 40,Factor IV, Coagulation
D054732 Calcium-Calmodulin-Dependent Protein Kinase Type 2 A multifunctional calcium-calmodulin-dependent protein kinase subtype that occurs as an oligomeric protein comprised of twelve subunits. It differs from other enzyme subtypes in that it lacks a phosphorylatable activation domain that can respond to CALCIUM-CALMODULIN-DEPENDENT PROTEIN KINASE KINASE. Ca(2+)-Calmodulin Dependent Protein Kinase Type II,CaCMKII,CaM KII,CaM KIIalpha,CaM KIIbeta,CaM KIIdelta,CaM Kinase II,CaM Kinase II alpha,CaM Kinase II beta,CaM Kinase II delta,CaM Kinase II gamma,CaM PK II,CaM-Kinase II,CaM-Kinase IIalpha,CaMKII,CaMKIIgamma,Calcium-Calmodulin Dependent Protein Kinase II beta,Calcium-Calmodulin Dependent Protein Kinase II delta,Calcium-Calmodulin Dependent Protein Kinase II gamma,Calcium-Calmodulin Protein Kinase II,Calcium-Calmodulin-Dependent PK Type II,Calcium-Calmodulin-Dependent Protein Kinase Type 2 alpha Subunit,Calcium-Calmodulin-Dependent Protein Kinase Type 2 beta Subunit,Calcium-Calmodulin-Dependent Protein Kinase Type 2 delta Subunit,Calcium-Calmodulin-Dependent Protein Kinase Type 2 gamma Subunit,Calcium-Dependent CaM Kinase II,Calmodulin Kinase IIalpha,Calmodulin-Dependent Protein Kinase II,CaM Kinase IIalpha,Calcium Calmodulin Dependent PK Type II,Calcium Calmodulin Dependent Protein Kinase II beta,Calcium Calmodulin Dependent Protein Kinase II delta,Calcium Calmodulin Dependent Protein Kinase II gamma,Calcium Calmodulin Dependent Protein Kinase Type 2,Calcium Calmodulin Dependent Protein Kinase Type 2 alpha Subunit,Calcium Calmodulin Dependent Protein Kinase Type 2 beta Subunit,Calcium Calmodulin Dependent Protein Kinase Type 2 delta Subunit,Calcium Calmodulin Dependent Protein Kinase Type 2 gamma Subunit,Calcium Calmodulin Protein Kinase II,Calcium Dependent CaM Kinase II,Calmodulin Dependent Protein Kinase II
D020134 Catalytic Domain The region of an enzyme that interacts with its substrate to cause the enzymatic reaction. Active Site,Catalytic Core,Catalytic Region,Catalytic Site,Catalytic Subunit,Reactive Site,Active Sites,Catalytic Cores,Catalytic Domains,Catalytic Regions,Catalytic Sites,Catalytic Subunits,Core, Catalytic,Cores, Catalytic,Domain, Catalytic,Domains, Catalytic,Reactive Sites,Region, Catalytic,Regions, Catalytic,Site, Active,Site, Catalytic,Site, Reactive,Sites, Active,Sites, Catalytic,Sites, Reactive,Subunit, Catalytic,Subunits, Catalytic

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