Engineering of ATP synthase for enhancement of proton-to-ATP ratio

Hiroshi Ueno (), Kiyoto Yasuda, Norie Hamaguchi-Suzuki, Riku Marui, Naruhiko Adachi, Toshiya Senda, Takeshi Murata and Hiroyuki Noji ()
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Hiroshi Ueno: The University of Tokyo
Kiyoto Yasuda: The University of Tokyo
Norie Hamaguchi-Suzuki: Chiba University
Riku Marui: The University of Tokyo
Naruhiko Adachi: High Energy Accelerator Research Organization (KEK)
Toshiya Senda: High Energy Accelerator Research Organization (KEK)
Takeshi Murata: Chiba University
Hiroyuki Noji: The University of Tokyo

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: Abstract FoF1-ATP synthase (FoF1) interconverts the energy of the proton motive force (pmf) and that of ATP through the mechanical rotation. The H+/ATP ratio, one of the most crucial parameters in bioenergetics, varies among species due to differences in the number of H+-binding c-subunits, resulting in H+/ATP ratios ranging from 2.7 to 5. In this study, we seek to significantly enhance the H+/ATP ratio by employing an alternative approach that differs from that of nature. We engineer FoF1 to form multiple peripheral stalks, each bound to a proton-conducting a-subunit. The engineered FoF1 exhibits an H+/ATP ratio of 5.8, surpassing the highest ratios found in naturally occurring FoF1s, enabling ATP synthesis under low pmf conditions where wild-type enzymes cannot synthesize ATP. Structural analysis reveals that the engineered FoF1 forms up to three peripheral stalks and a-subunits. This study not only provides valuable insights into the H+-transport mechanism of FoF1 but also opens up possibilities for engineering the foundation of cellular bioenergetics.

Date: 2025
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DOI: 10.1038/s41467-025-61227-w

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