A domain-swapped CaMKII conformation facilitates linker-mediated allosteric regulation

Bao V. Nguyen, Can Özden, Kairong Dong, Oguz Can Koc, Ana P. Torres-Ocampo, Noelle Dziedzic, Daniel Flaherty, Jian Huang, Saketh Sankara, Nikki Lyn Abromson, Diana R. Tomchick, Rafael A. Fissore, Jianhan Chen, Scott C. Garman and Margaret M. Stratton ()
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Bao V. Nguyen: University of Massachusetts
Can Özden: University of Massachusetts
Kairong Dong: University of Massachusetts
Oguz Can Koc: University of Massachusetts
Ana P. Torres-Ocampo: University of Massachusetts
Noelle Dziedzic: University of Massachusetts
Daniel Flaherty: University of Massachusetts
Jian Huang: University of Massachusetts
Saketh Sankara: University of Massachusetts
Nikki Lyn Abromson: University of Massachusetts
Diana R. Tomchick: University of Texas Southwestern Medical Center
Rafael A. Fissore: University of Massachusetts
Jianhan Chen: University of Massachusetts
Scott C. Garman: University of Massachusetts
Margaret M. Stratton: University of Massachusetts

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Memory formation, fertilization, and cardiac function rely on precise Ca2+ signaling and subsequent Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation. Ca2+ sensitivity of the four CaMKII paralogs in mammals is linked to the length of the variable linker region that undergoes extensive alternative splicing. In this study, we determine that the position of charged residues within the linker modulates the Ca2+/CaM sensitivity. We present an X-ray crystal structure of the full-length CaMKIIδ holoenzyme consisting of domain-swapped dimers within a dodecameric complex, revealing potential contacts for cooperativity and allostery. Based on molecular dynamics (MD) simulations, small-angle X-ray scattering (SAXS) measurements, and live-cell imaging, we propose a model where the domain-swapped conformation positions the charges of the linker region to drive an interaction with the regulatory segment that modulates the degree of autoinhibition. Our findings provide a framework for understanding allosteric regulation of CaMKII by the linker region in Ca2+-sensitive cells.

Date: 2025
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DOI: 10.1038/s41467-025-63249-w

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