Kanazawa University research: High-speed AFM and 3D modelling help towards understanding the dynamics of a protein implicated in several cancers
An enzyme type noted in several cancers is the family of adenosine deaminases acting on RNA (ADARs). These enzymes convert adenosines in double-stranded RNA (dsRNA) into inosines, which cells read as guanosines. As such, ADARs can contribute to changes in protein-coding sequences and diminish the robustness of various RNA processes. Studies have shown that silencing one type of ADAR – ADAR1 – can prevent cancer proliferation and sensitize cancers to immunotherapy, suggesting that they could be a promising target for cancer treatments.
However, so far, it has been difficult to pin down information on the structural dynamics of ADAR1 due to its size and complexity. Now, researchers led by Madhu Biyani at Kanazawa University, WPI-NanoLSI, Yasuhiro Isogai at Toyama Prefectural University, and Manish Biyani at Ishikawa Create Labo and Kwansei Gakuin University have combined high-speed atomic force microscopy (HS-AFM) and 3D modelling to shed light on the enzyme's conformations and interactions with dsRNA.
Like many proteins, ADAR1 functions through changes in its conformation. However, most experimental techniques for determining protein structure, as well as 3D modelling algorithms, give static or average conformations that obscure the structural dynamics so important to the protein's function. Combining 3D modelling with HS-AFM proved helpful in shedding light on these dynamic aspects of ADAR1.
The researchers first used 3D modelling based on the machine learning algorithm AlphaFold2 to predict the conformations of the enzyme and noted that it could take the form of monomers, dimers, trimers, and tetramers. HS AFM observations, as well as theoretically simulated HS AFM, supported these initial conclusions regarding the possible oligomer formations.
The researchers then looked at the conformations the enzyme formed in the presence of double-stranded RNA (dsRNA). In particular, the researchers focused on a certain aryl hydrocarbon receptor 3'UTR mRNA as the target for ADAR1, since this receptor is known to be involved in the metabolism of substances alien to the body at those points. Observations of the dsRNA with HS-AFM not only agreed with previous structural studies but were able to provide insights into the structure of the target region in particular.
Thanks to the speed and resolution of the HS-AFM image capture, the researchers were able to identify different conformations in the proteins that seemed to relate to distinct phases of the deaminizing process. In their report of the work, the researchers explain how ADAR1 first "searches" for the dsRNA and on "recognizing" it, adopts a flexible conformation as it approaches. The enzyme then engages in what the researchers describe as "capture" of the dsRNA backbone, for which the conformation transitions to something more stable and "anchor-like". The researchers highlight the role of dsRNA binding domains (dsRBDs) to stabilize the interaction with the dsRNA at this stage. They also note "a visibly large interfacial interaction between the deaminase domains, forming a dimer" as the enzyme dimer loops out on the dsRNA. The enzyme subsequently scans the RNA and dissociates to search for adenosine sites to convert.
"These observations suggest that the dsRBDs are critical for initiating interactions between the deaminase domains, thereby promoting the formation of a stable, functional dimeric complex capable of efficiently binding and catalyzing the editing of dsRNA substrates," the researchers conclude in their report, thereby flagging the insights this study offers for further work towards possible cancer therapeutics.
The researchers further propose future studies to compare ADAR1 and ADAR2, and to perform mutation analyses to clarify how ADAR1 dimerization influences A-to-I RNA editing, ultimately aiming to develop effective ADAR1 inhibitors.
Figure 1: Three-dimensional modeling analysis of ADAR1 oligomerization.https://nanolsi.kanazawa-u.ac.jp/wp/wp-content/uploads/Fig.-1_Nat.-Commun._Jun.-2025.jpg© 2025 Biyani, et al., Nature Communications
Figure 2: Simulated AFM images of ADAR1 oligomerization.https://nanolsi.kanazawa-u.ac.jp/wp/wp-content/uploads/Fig.-2_Nat.-Commun._Jun.-2025.jpg© 2025 Biyani, et al., Nature Communications
Glossary
Atomic force microscopy
This imaging technique uses a nanosized tip at the end of a cantilever that is scanned over a sample. It can be used to determine the topography of a sample surface from the change in the strength of forces between the tip and the sample with distance, and the resulting deflection of the cantilever. It was first developed in the 1980s, but a number of modifications have augmented the functionality of the technique since. It is better suited to imaging biological samples than the scanning tunnelling microscope that had been previously developed because it does not require a conducting sample.
In the 2000s, Toshio Ando at Kanazawa University was able to improve the scanning speed to such an extent that moving images could be captured. This allowed people to use the technique to visualize dynamic molecular processes for the first time.
ADARs
Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine, which is interpreted by cells as guanosine. This editing can influence alternative splicing, miRNA processing, double-stranded RNA stability, and protein-coding sequences. In mammals, there are two known ADARs responsible for adenosine to inosine RNA editing – ADAR1 and ADAR2. Notably, overexpression and increased activity of ADAR1 have been observed in cancers of the liver, breast, esophagus, prostate, and bone marrow.
3D modelling
Several techniques are now available for protein structure prediction. In this study, the researchers used AlphaFold2 to model the structure of human ADAR1. Due to disorder regions in the N-terminal 822 residues, the final model focused on residues 823-1226, which encompass the deaminase domain. This monomer model served as the basis for building higher-order structures—dimer, trimer, tetramer, and polymer by superimposing it onto the ADAR2 dimer structure (PDB ID:1ZY7) through sequence alignment. Since determining ADAR1's full structure is challenging due to its size and complexity, the better-characterized ADAR2 provided a template to generate ADAR1 multimer models.
Reference
Madhu Biyani, Yasuhiro Isogai, Kirti Sharma, Shoei Maeda, Hinako Akashi, Yui Sugai, Masataka Nakano, Noriyuki Kodera, Manish Biyani, Miki Nakajima, High-speed atomic force microscopy and 3D modeling reveal the structural dynamics of ADAR1 complexes, Nature Communications 16, 4757 (2025).
DOI：10.1038/s41467-025-59987-6
URL: https://www.nature.com/articles/s41467-025-59987-6
Funding and AcknowledgementsFinancial support from the Grants-in-Aid for Scientific Research (C), KAKENHI, Japan Society for the Promotion of Science (JSPS) (23K06067 to MadhuB), and the World Premier International Research Center Initiative (WPI), MEXT, Japan, are gratefully acknowledged. The authors thank Prof. Toshio Ando, Dr. Kenichi Umeda, Ms. Wei Weilin, Ms. Aimi Makino, and Ms. Kayo Nagatani for their technical support of HS-AFM experiments.
Contact
Kimie Nishimura (Ms)Project Planning and Outreach, NanoLSI Administration OfficeNano Life Science Institute, Kanazawa UniversityEmail: nanolsi-office@adm.kanazawa-u.ac.jpKakuma-machi, Kanazawa 920-1192, Japan
About Nano Life Science Institute (WPI-NanoLSI), Kanazawa UniversityUnderstanding nanoscale mechanisms of life phenomena by exploring "uncharted nano-realms".
Cells are the basic units of almost all life forms. We are developing nanoprobe technologies that allow direct imaging, analysis, and manipulation of the behavior and dynamics of important macromolecules in living organisms, such as proteins and nucleic acids, at the surface and interior of cells. We aim at acquiring a fundamental understanding of the various life phenomena at the nanoscale.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 globally visible research centers boasting the highest standards and outstanding research environments. Numbering more than a dozen and operating at institutions throughout the country, these centers are given a high degree of autonomy, allowing them to engage in innovative modes of management and research. The program is administered by the Japan Society for the Promotion of Science (JSPS).
See the latest research news from the centers at the WPI News Portal:https://www.eurekalert.org/newsportal/WPIMain WPI program site: www.jsps.go.jp/english/e-toplevel
About Kanazawa UniversityAs the leading comprehensive university on the Sea of Japan coast, Kanazawa University has contributed greatly to higher education and academic research in Japan since it was founded in 1949. The University has three colleges and 17 schools offering courses in subjects that include medicine, computer engineering, and humanities.
The University is located on the coast of the Sea of Japan in Kanazawa, a city rich in history and culture. The city of Kanazawa has a highly respected intellectual profile since the time of the fiefdom (1598-1867). Kanazawa University is divided into two main campuses: Kakuma and Takaramachi for its approximately 10,200 students, including 600 from overseas.http://www.kanazawa-u.ac.jp/en/
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