CaMKIIα holoenzymes self-organize into chain-like mesoscale clusters
Calcium- and calmodulin-dependent protein kinase II (CaMKII) is highly enriched in dendritic spines at concentrations comparable to those of cytoskeletal proteins and plays a central role in synaptic plasticity. During long-term potentiation, CaMKIIα further accumulates in spines. However, the mechanisms governing its higher-order organization remain poorly understood. Here, we use high-speed atomic force microscopy to visualize interholoenzyme interaction of CaMKIIα at mesoscopic scales (5 to 500 nanometers). Under freely diffusible conditions, CaMKIIα holoenzymes do not form stable clusters. In contrast, when spatially confined, they assemble into chain-like clusters mediated by kinase-domain interactions. These clusters expand upon activation, concomitant with the dissociation of the regulatory segment. Notably, the CaMKIIα Pro 212 →Leu (P212L) mutant associated with neurodevelopmental disorders forms extensive clusters even in the basal state. Together, our findings demonstrate that CaMKIIα-CaMKIIα interactions drive mesoscale cluster formation and that precise regulation of cluster size and activation-dependent growth might be critical for synaptic signaling.
Authors
- Taisei Suzuki (ORCID: https://orcid.org/0009-0009-4423-2819)
- Kenichi Umeda (ORCID: https://orcid.org/0000-0002-3650-3828)
- Carsten Beta (ORCID: https://orcid.org/0000-0002-0100-1043)
- Takashi Sumikama (ORCID: https://orcid.org/0000-0003-3696-5720)
- Ayumi Sumino (ORCID: https://orcid.org/0000-0001-9385-0431)
- Tamoghna Das (ORCID: https://orcid.org/0000-0001-7112-2820)
- Noriyuki Kodera (ORCID: https://orcid.org/0000-0003-4880-8423)
- Mikihiro Shibata (ORCID: https://orcid.org/0000-0001-5041-3979)
- Hideji Murakoshi (ORCID: https://orcid.org/0000-0002-8938-368X)
- Kodai Hasegawa
- Keisuke Matsushima (ORCID: https://orcid.org/0009-0005-0407-8723)
Institutions
- Kanazawa University (JP)
- University of Potsdam (DE)
- The Graduate University for Advanced Studies, SOKENDAI (JP)
- Kyoto University (JP)
- Life Science Institute (JP)
- National Institute for Physiological Sciences (JP)
Publication Details
- Journal
- Science Advances
- Published
- 2026-09-11
- DOI
- https://doi.org/10.1126/sciadv.aeg0958
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Support for Pioneering Research Initiated by the Next Generation
- Naito Foundation
- Takeda Science Foundation
- Uehara Memorial Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Japan Society for the Promotion of Science
- Core Research for Evolutional Science and Technology
- Exploratory Research for Advanced Technology