A domain-swapped CaMKII conformation facilitates linker-mediated allosteric regulation
Memory formation, fertilization, and cardiac function rely on precise Ca<sup>2+</sup> signaling and subsequent Ca<sup>2+</sup>/calmodulin-dependent protein kinase II (CaMKII) activation. Ca<sup>2+</sup> 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 Ca<sup>2+</sup>/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 Ca<sup>2+</sup>-sensitive cells.
Authors
- Ana P. Torres‐Ocampo (ORCID: https://orcid.org/0000-0003-1223-7120)
- Diana R. Tomchick (ORCID: https://orcid.org/0000-0002-7529-4643)
- Bao V. Nguyen (ORCID: https://orcid.org/0000-0002-4693-3098)
- Can Özden (ORCID: https://orcid.org/0000-0002-5673-878X)
- Jian Huang (ORCID: https://orcid.org/0000-0003-0149-1799)
- Scott C. Garman (ORCID: https://orcid.org/0000-0001-9912-2670)
- Rafael A. Fissore (ORCID: https://orcid.org/0000-0001-5655-0915)
- Jianhan Chen (ORCID: https://orcid.org/0000-0002-5281-1150)
- Daniel P. Flaherty (ORCID: https://orcid.org/0000-0002-8305-0606)
- Noelle Dziedzic (ORCID: https://orcid.org/0000-0001-7517-1873)
- Margaret M. Stratton (ORCID: https://orcid.org/0000-0003-2686-9022)
- Nikki Lyn Abromson (ORCID: https://orcid.org/0009-0002-4212-7547)
- Kairong Dong (ORCID: https://orcid.org/0009-0009-7939-1377)
- Oguz Can Koc
- Saketh Sankara
Institutions
- University of Massachusetts Amherst (US)
- Interface (United States) (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-26
- DOI
- https://doi.org/10.1038/s41467-025-63249-w
- Primary Topic
- Ion channel regulation and function
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Energy
- University of Chicago
- National Institutes of Health
- Basic Energy Sciences
- Biological and Environmental Research
- Argonne National Laboratory
- Lawrence Berkeley National Laboratory