First person – Shigetaka Nishiguchi

Shigetaka Nishiguchi

How would you explain the main findings of your paper in lay terms?

Cell–cell adhesion in humans and other animals is regulated by members of the classical cadherin family. While classical cadherins are common among animals, their domain composition and organization in the extracellular part has evolved divergently through domain losses from an ancestral state in the lineages leading to mammals and insects. To understand the structural diversity of classical cadherins, we applied high-speed atomic force microscopy (HS-AFM), which can observe nanometer-scale structures and dynamics of proteins in solution. We compared an ancestral long cadherin and a derived short cadherin in insects. We found that the long cadherin has a complicated bent and dynamically changeable structure, in contrast to the simpler structure of the short cadherin. Our findings suggest that dramatic changes in the classical cadherin structure responsible for cell–cell adhesion have occurred during animal evolution.

Were there any specific challenges associated with this project? If so, how did you overcome them?

For AFM imaging, proteins should be adsorbed firmly on a substrate, because the scanning probe needs to be in contact with the protein to reproduce its surface topography. However, to analyze structural dynamics of proteins, they should not adsorb too strongly on the substrate, otherwise the motion of the proteins is impeded. To reconcile these opposing criteria, I tried various buffer compositions and fine-tuned the electrostatic interaction between proteins and the substrate. Eventually, I found optimized imaging conditions and succeeded in observing the structural dynamics of cadherin.

When doing the research, did you have a particular result or ‘eureka’ moment that has stuck with you?

When I succeeded in observing the structure and dynamics of ancestral-type classical cadherin and found that cadherin has several kinked portions, a highly flexible hinge and a large globular portion, I was very surprised by these structural features, which I had never seen before. They are totally missing in mammalian classical cadherins.

Why did you choose Journal of Cell Science for your paper?

I have read a lot of important papers about cadherin and cell–cell adhesion in Journal of Cell Science. I also agree very much with the journal's initiatives to promote the research community. We think that Journal of Cell Science has a large audience who may be interested in our research.

Have you had any significant mentors who have helped you beyond supervision in the lab? How was their guidance special?

The first mentor is Dr Hiroki Oda, who was my supervisor when I did the research for this article as a graduate student. He focuses on independence of young scientists and encouraged me from an early stage onwards to think by myself about how the research could be progressed. The second mentor is Dr Katsunori Ogo, who was a senior colleague when I worked in a private company. He strictly viewed his colleagues' expertise and, therefore, I often thought I should learn more about my research during discussions with him. I remember he often said that a person who holds a PhD must continue to deepen their knowledge in order to increase human prosperity. Both mentors had a huge impact on my research career.

What motivated you to pursue a career in science, and what have been the most interesting moments on the path that led you to where you are now?

I get excited when I come across a new idea or finding during experiments and discussions about my research, which encourages me to make further efforts. When I observed the structural dynamics of classical cadherin by HS-AFM for the first time, I thought I could explore nanometer-scale structural dynamics of cell–cell adhesion, which is not well understood so far.

What's next for you?

I decided to leave a private company and join academia to progress my research and gain independence as a researcher. Now, I study under the supervision of Dr Takayuki Uchihashi, who is a distinguished scientist in the field of HS-AFM. He strongly encourages independence of young scientists, and I am working in his laboratory to investigate my own ideas. Currently, I'm mainly trying to develop a reconstitution experiment using proteins for HS-AFM imaging, and multi-modal HS-AFM for cell measurement. I believe there are many applications for HS-AFM in cell biological studies.

Tell us something interesting about yourself that wouldn't be on your CV

I like spending time with my wife and daughter during holidays, and I love going to amusement places to play claw machines with my family. My daughter loves the stuffed toys I get from the claw machines, and we have a lot of such toys (probably over 30). I can quickly judge whether a claw machine can catch a toy or not at first sight. Research in academia is highly competitive and stressful. Sometimes these stressful situations impede creativity for research. I can relax and think about my research thanks to playing claw machines with my family.