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dc.contributor.authorOzden, Can
dc.contributor.authorSloutsky, Roman
dc.contributor.authorMitsugi, Tomohiro
dc.contributor.authorSantos, Nicholas
dc.contributor.authorAgnello, Emily
dc.contributor.authorGaubitz, Christl
dc.contributor.authorFoster, Joshua
dc.contributor.authorLapinskas, Emily
dc.contributor.authorEsposito, Edward A.
dc.contributor.authorSaneyoshi, Takeo
dc.contributor.authorKelch, Brian A
dc.contributor.authorGarman, Scott C.
dc.contributor.authorHayashi, Yasunori
dc.contributor.authorStratton, Margaret M.
dc.date2022-08-11T08:08:28.000
dc.date.accessioned2022-08-23T15:56:03Z
dc.date.available2022-08-23T15:56:03Z
dc.date.issued2021-10-30
dc.date.submitted2021-12-01
dc.identifier.citation<p>bioRxiv 2020.10.25.354241; doi: https://doi.org/10.1101/2020.10.25.354241. <a href="https://doi.org/10.1101/2020.10.25.354241" target="_blank" title="view preprint in biorxiv">Link to preprint on bioRxiv.</a></p>
dc.identifier.doi10.1101/2020.10.25.354241
dc.identifier.urihttp://hdl.handle.net/20.500.14038/29888
dc.description<p>This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.</p> <p>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.</p>
dc.description.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.
dc.language.isoen_US
dc.relationNow published in Cell Reports doi: 10.1016/j.celrep.2022.111064
dc.relation.urlhttps://doi.org/10.1101/2020.10.25.354241
dc.rightsThe 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.
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectBiochemistry
dc.subjectCa2+/calmodulin dependent protein kinase II
dc.subjectlong-term memory formation
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectBiochemistry
dc.subjectEnzymes and Coenzymes
dc.titleCaMKII binds both substrates and activators at the active site [preprint]
dc.typePreprint
dc.source.journaltitlebioRxiv
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=3124&amp;context=faculty_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/2094
dc.identifier.contextkey26418149
refterms.dateFOA2022-08-23T15:56:04Z
html.description.abstract<p>Ca<sup>2+</sup>/calmodulin dependent protein kinase II (CaMKII) is a signaling protein that is required for long-term memory formation. Ca<sup>2+</sup>/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.</p>
dc.identifier.submissionpathfaculty_pubs/2094
dc.contributor.departmentBiochemistry and Molecular Biotechnology


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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.
Except where otherwise noted, this item's license is described as 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.