Unique underpinnings revealed for stomach’s acid pump

Nagoya University researchers and colleagues have improved understanding of the molecular mechanisms of a key protein that makes the stomach acidic. Their findings, published in the journal Nature Communications, could lead to better drugs for stomach ulcers and shed light on the functions of similar proteins across the human body.“This gastric protein pumps in acidic ions to fortify our stomach, which is important for digestion but can sometimes lead to ulcers. Our results improve our understanding of how these types of proteins work, and we expect them to have further applications in drug development,” says Kazuhiro Abe, a protein crystallographer at Nagoya University who led the research.

The H⁺/K⁺ ATPase protein is an enzyme that pumps hydrogen ions (H⁺) into the stomach to help digestion and kill any bugs we might swallow with our food and drink. However, excessive stomach acidification can lead to ulcers. Drugs that block the enzyme’s activity could therefore reduce acidification and ease ulcer symptoms.

To design more effective drugs, scientists need to know how the protein works. In this study, the researchers demonstrated it has an unusual feature. To pump the hydrogen ions into the stomach, the protein first needs to bind to a potassium ion (K⁺). Similar proteins typically bind two such potassium ions to trigger the pump mechanism. But H⁺/K⁺ ATPase needs only one.

To investigate, the scientists fabricated novel versions of the protein. By adding five amino acids at specific locations, and then studying the new structure with a cryo-electron microscope, they fabricated a mutant form of H⁺/K⁺ ATPase that bound to two potassium ions.

The findings will help scientists understand why these important pump proteins bind to different numbers of ions. They can use that information to unpick the molecular mechanisms of similar proteins elsewhere.

“We have many cation [ion with a positive charge] pumps in our body. Sodium (Na⁺) pumps keep cells alive and drive signaling in the nervous system. Calcium (Ca⁺) pumps are vital for muscle contraction,” Abe says. “Our strategy would be useful to investigate the cation selectivity for each cation pump, which is a central question for scientists working on the cation transport proteins.”

The study, Gastric proton pump with two occluded K+ engineered with sodium pump-mimetic mutations," was published in the journal Nature Communications on September 29, 2021 at DOI: 10.1038/s41467-021-26024-1. 

About Nagoya University, Japan

Nagoya University has a history of about 150 years, with its roots in a temporary medical school and hospital established in 1871, and was formally instituted as the last Imperial University of Japan in 1939. Although modest in size compared to the largest universities in Japan, Nagoya University has been pursuing excellence since its founding. Six of the 18 Japanese Nobel Prize-winners since 2000 did all or part of their Nobel Prize-winning work at Nagoya University: four in Physics - Toshihide Maskawa and Makoto Kobayashi in 2008, and Isamu Akasaki and Hiroshi Amano in 2014; and two in Chemistry - Ryoji Noyori in 2001 and Osamu Shimomura in 2008. In mathematics, Shigefumi Mori did his Fields Medal-winning work at the University. A number of other important discoveries have also been made at the University, including the Okazaki DNA Fragments by Reiji and Tsuneko Okazaki in the 1960s; and depletion forces by Sho Asakura and Fumio Oosawa in 1954.

Website: http://en.nagoya-u.ac.jp/