Biologist gets a taste for novel protein research

2 October 2019

A Croucher scholar pursuing his DPhil at the University of Oxford has been involved in research that has revealed, for the first time, the structural detail of a novel protein family that plays a role in sour taste reception and inner-ear balance.

Using cryogenic electron microscopy (cryo-EM), an advanced imaging technology, researchers from Scripps Research, in collaboration with scientists at the University of Southern California and University of Oxford, gained crucial structural and functional insights into the recently discovered proteins, known as otopetrins. These may have many other important roles in human health as they have also been found to be prevalent in the digestive tract and immune system.

The new study, revealing an unprecedented level of structural detail for these proteins, has appeared in Nature Structural & Molecular Biology.

Mr Alex Che Chun Tsui (Croucher Scholarship 2017), a member of biophysicist Mark Sansom’s team at Oxford, conducted molecular simulations to discern how cholesterol and water molecules interact dynamically with otopetrins.

Otopetrins are among a class of proteins known as ion channels, which selectively allow small molecules called ions to pass through a cell’s outer membrane. They are unique in that they permit hydrogen ions to cross the membrane, whereas other ion channels allow sodium or potassium to cross.

Previous research led by Emily Liman, from the University of Southern California, showed that otopetrins function as proton channels, which are a subset of ion channels, and uncovered their likely role in sensing acids as part of sour taste perception. The researchers noticed that otopetrins were highly expressed throughout the body, including in the digestive system, which led them to think these proteins may offer a route to treat conditions such as inflammatory bowel disease.

With the goal of gleaning new insights into how these channels function, the team reached out to Professor Andrew Ward, of the Department of Integrative Structural and Computational Biology at Scripps Research. Liman’s lab cloned additional species variants of otopetrins and conducted functional studies to support Ward’s structural work, while Sansom’s team carried out the molecular simulations.

Through the use of the cryo-EM imaging technology, the researchers characterised otopetrin structures from zebrafish and chicken. This allowed them to see that the assembled protein is formed of two identical sub-units, and to start to resolve how ions could move through the channel.

Top and side views of cryo-EM density map of the Otopetrin 3 (Otop3) orthologue from chicken. The homodimeric structure (green and purple) of Otop3 is surrounded by lipids and cholesterols (yellow).

They also resolved an exceptional number of protein-lipid interactions, an increasingly hot topic in membrane protein research, as the combination of cryo-EM and molecular simulations allows these to be probed in detail.

Now that the team has defined the structure of the proton channels, it plans to probe the structure at even higher resolution to observe water molecules and ions that are critical for function but typically very difficult to observe.

Ward’s Scripps Research team, which Tsui will soon join, hopes to move on from using otopetrin protein channels from zebrafish and chickens to conducting research with human samples, with exciting implications for further studies related to human health and disease.

Alex Che Chun Tsui is reading for his joint DPhil and PhD degrees at the University of Oxford, working with Prof Mark Sansom, before relocating to Scripps Research (California) in 2020 to work with Prof Andrew Ward. Tsui graduated with a MSc ETH in Biology (Structural Biology & Biophysics) from the Swiss Federal Institute of Technology Zurich (ETH Zürich). Prior to that, he completed his BSc in Biochemistry at University College London with First Class Honours (Dean’s List). Alex was awarded a Croucher Scholarship in 2017.

To view Alex Tsui’s Croucher profile, please click here.