Kanazawa University research: High-speed AFM imaging reveals how brain enzyme forms dodecameric ring structure

KANAZAWA, Japan, Dec. 26, 2025 /PRNewswire/ -- Scientists at the Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, have captured real-time images showing how a key brain enzyme organizes itself to help memory formation. Their study, published in Nature Communications, reveals that the enzyme CaMKII forms mixed α/β subunit structures whose interactions stabilize learning-related signals in neurons.

A molecular switch for learning

One of the brain's most important enzymes for learning and memory is Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). This enzyme acts like a molecular switch, turning signals on and off to help nerve cells strengthen their connections — a process known as synaptic plasticity.

When we learn, the links between neurons, called synapses, are reinforced. CaMKII drives this change by reorganizing and activating molecules inside these synapses.

CaMKII is made up of 12 protein subunits arranged in a ring. Two types of subunits — α (alpha) and β (beta) — are mixed in different amounts in various regions of the brain. Scientists have long suspected that the precise balance between these two forms is important for memory formation, but until now, no one had actually seen how the α and β subunits combine and function together inside the enzyme's structure.

Filming molecules in motion

Using high-speed atomic force microscopy (HS-AFM), the Kanazawa University team led by Mikihiro Shibata filmed the dynamic movements of CaMKII at the single-molecule level. The images revealed that α and β subunits mix within the 12-unit ring in a 3:1 ratio, closely matching the natural composition found in the mammalian forebrain.

The researchers also found that β subunits preferentially positioned themselves next to each other, with an 83% probability of adjacency, forming small clusters within the enzyme's ring structure.

Stable molecular memory

When the enzyme was activated by calcium and calmodulin—signals associated with neuronal activity—these adjacent β subunits formed stable 'kinase domain complexes' that persisted for extended periods.

This structure reduced the enzyme's overall catalytic activity but maintained an open surface that could continue to interact with other proteins, allowing memory-related signaling to persist even after the initial calcium signal faded.

"Our high-speed AFM movies show how CaMKII reorganizes itself at the molecular level to stabilize memory signals," says Shibata. "The β subunits act like anchors that hold the enzyme in an active, memory-supporting configuration."

Experimental approach

Implications and next steps

The findings provide new insight into the molecular architecture of memory and open possibilities for studying how mutations or subunit imbalances in CaMKII contribute to neurological and psychiatric disorders.

The team plans to extend their HS-AFM studies to observe how CaMKII interacts with actin filaments and synaptic receptors such as NMDAR, which link the enzyme's activity to changes in neuronal shape and connectivity.

Glossary

Reference

Keisuke Matsushima, Takashi Sumikama, Taisei Suzuki, Mizuho Ito, Yutaro Nagasawa, Ayumi Sumino, Holger Flechsig, Tomoki Ogoshi, Kenichi Umeda, Noriyuki Kodera, Hideji Murakoshi, and Mikihiro Shibata. "Structural dynamics of mixed-subunit CaMKIIα/β heterododecamers filmed by high-speed AFM."

Nature Communications 16, 10603 (2025).

DOI: 10.1038/s41467-025-66527-9

URL: https://www.nature.com/articles/s41467-025-66527-9 

This work was supported by the World Premier International Research Center Initiative (WPI), Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, JSPS KAKENHI (JP24K21942, JP25H00972, JP22H04926 Advanced Bioimaging Support (ABiS) , JP23H0424, JP24H01298), and grants from the Mochida Memorial Foundation for Medical and Pharmaceutical Research, Uehara Memorial Foundation, Naito Foundation, JST CREST (JPMJCR1762 to N.K. and H.F.), JST SPRING (JPMJSP2135), and JST ERATO (JPMJER2403).

Kimie Nishimura (Ms.)Project Planning and Outreach, NanoLSI Administration OfficeNano Life Science Institute, Kanazawa UniversityKakuma-machi, Kanazawa 920-1192, JapanEmail: [email protected] 

Nano Life Science Institute (WPI-NanoLSI), Kanazawa University

Understanding nanoscale mechanisms of life phenomena by exploring "uncharted nano-realms." Cells are the basic units of life. At NanoLSI, researchers develop nanoprobe technologies that enable direct imaging, analysis, and manipulation of biomolecules such as proteins and nucleic acids inside living cells. By visualizing these processes at the nanoscale, the institute seeks to uncover fundamental principles of life and disease.

https://nanolsi.kanazawa-u.ac.jp/en/ 

About the World Premier International Research Center Initiative (WPI)

The WPI program was launched in 2007 by Japan's Ministry of Education, Culture, Sports, Science and Technology (MEXT) to foster world-class research centers with outstanding research environments. WPI centers enjoy a high degree of autonomy, enabling innovative management and global collaboration. The program is administered by the Japan Society for the Promotion of Science (JSPS).

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About Kanazawa University

Founded in 1862 in Ishikawa Prefecture, Kanazawa University is one of Japan's leading comprehensive national universities with a history spanning more than 160 years. With campuses at Kakuma and Takaramachi–Tsuruma, the university upholds its guiding principle of being "a research university dedicated to education, while opening its doors to both local and global society."

Internationally recognized for its research institutes, including the Nano Life Science Institute (WPI-NanoLSI) and the Cancer Research Institute, Kanazawa University promotes interdisciplinary research and global collaboration, driving progress in health, sustainability, and culture.

http://www.kanazawa-u.ac.jp/en/

SOURCE Kanazawa University