University of Tokyo
AsianScientist (May. 4, 2020) – At the turn of the 20th century, American architect Louis Sullivan—hailed as the father of skyscrapers—coined the famous maxim “form follows function.” In other words, a building’s shape should reflect its purpose.
The same tenet holds true not just for towering skyscrapers, but also for biological molecules at the smallest scale. By decoding the structures of the molecules necessary for life, generations of scientists have gained a deeper understanding of the molecular mechanisms that quietly govern our lives.
Professor Chikashi Toyoshima of the University of Tokyo has devoted his research career to discovering the structural basis for the functions of just two proteins: the calcium and sodium-potassium pumps. These tiny machines transport ions in and out of our cells—and in doing so, trigger crucial processes like muscle relaxation and heart contraction.
In his work, Toyoshima uses a combination of electron microscopy (EM) and X-ray crystallography, a technique that uses X-rays to reveal the three-dimensional structure of a molecule. Despite his singular focus on the two aforementioned pumps, his dedication has taken him far. For his fundamental contributions to understanding the biology of protein pumps, Toyoshima was awarded the 2018 Imperial Prize and Japan Academy Prize.
Speaking to Asian Scientist Magazine, Toyoshima traces his serendipitous journey from prospective medical student to crystallography pioneer, and shares with us the lessons he learnt along the way.
- How did you go from potentially becoming a medical doctor to visualizing proteins at the smallest scale?
- For nearly three decades, you have been working almost exclusively on two proteins: the calcium pump and sodium-potassium pump. What sparked your initial interest in working on these two proteins?
- Exactly 20 years ago, you published the first high-resolution crystal structure of an ion pump in Nature. Can you recount to us the Eureka moment behind this achievement?
- How can you explain the significance of your work to a layperson?
- What challenges did you encounter on the journey to understanding the two ion pumps? How did you overcome these challenges?
- What else are you hoping to understand about the calcium and sodium-potassium pumps?
- What is your research philosophy?
- What advice can you share for aspiring scientists in Asia?
As my elder brother chose to enter medicine, I thought my family didn’t need two medical doctors. So I decided to do biophysics at the University of Tokyo. One summer, I visited Professor [Setsuro] Ebashi’s lab and was fascinated by the 3D image reconstruction of muscle filaments from electron micrographs. I thought the technique had great potential and wanted to become an electron microscopist. I learned crystallography later on.
When I was at the MRC Laboratory of Molecular Biology at Cambridge, UK, I devised a way to reconstruct a 3D image from an electron micrograph of a tubular crystal. I also succeeded in the first resolution of the receptor for acetylcholine, a neurotransmitter that plays an important role in brain and muscle function. I wanted to apply the technique to another protein, and serendipitously, a colleague had tubular crystals of the calcium pump. The sodium-potassium pump came into my scope of interest much later.
No technology existed at that time to analyze the tiny crystals of the calcium pump. I had three options: If I made the crystals much larger, I could use X-ray crystallography. If I made them just a few layers thick, I could turn to electron microscopy (EM). Or I could develop a new technology entirely.
I decided to pursue all three. The first strategy turned out to be the most successful, yet the results from all three ways reinforced one another and converged into a single solution. A very exciting time for a scientist!
I discovered the mechanism of ion pumping based on atomic structures. I also devised a way to crystallize membrane proteins in a lipid bilayer, that is, close to their native environment. This allows us to gain deeper insight into the protein’s structure and function in its natural state. That is why I received the 2016 Aminoff Prize.
Crystallization is always challenging as membrane proteins undergo large structural changes. But even harder is understanding the atomic structure obtained. Why does it look like that and how did the structural changes happen? For instance, the sodium and calcium ions have very similar radiuses—0.95 Å and 0.99 Å—respectively. But why can’t sodium bind to the calcium binding site in the calcium pump? The answer isn’t obvious.
Atomic structures help address fundamental questions. For instance, the calcium pump absolutely requires that two calcium-binding sites are filled for the transfer of a chemical group known as phosphoryl to take place. How then is premature phosphoryl transfer prevented? I think I can now address such questions, as I have (almost) enough atomic structures of the calcium pump in different states.
Solving for atomic structures requires technology and luck, but not much scientific techniques. Even a student can do that. Understanding the structure in the context of its function, however, requires thinking and knowledge. Figuring out underlying principles requires insights. Only a real scientist can do that.
If you work hard, good luck will come your way. But it also depends on your skill and insight. If you want to carry out research that other people cannot, you need to acquire your own unique skills and way of thinking. I think I made a right decision to learn physics as an undergraduate.
This article is from a monthly series called Asia’s Scientific Trailblazers. Click here to read other articles in the series.
Copyright: Asian Scientist Magazine; Photo: Chikashi Toyoshima.
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