2. Academic Validation
  3. Assembly and cooperative mechanism of the hexameric fungal plasma membrane H+-ATPase

Assembly and cooperative mechanism of the hexameric fungal plasma membrane H+-ATPase

  • Cell Rep. 2025 Jun 24;44(6):115753. doi: 10.1016/j.celrep.2025.115753.
Zi-Long You 1,  Yue-Ran Ni 1,  Yinggai Song 2,  Hua Li 3,  Kun-Zhao Liu 1,  Le-Xuan Wang 1,  Chao-Ran Zhao 4,  Peng Zhao 1,  Dan-Dan Chen 1,  Lin Wang 5,  Kai Wang 6,  Pengyan Xia 6,  Yu-Cheng Gu 7,  Caihong Yun 1,  Lin Bai 8
Affiliations

Affiliations

  • 1 Department of Biophysics, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
  • 2 Peking University First Hospital, Peking University, Beijing 100034, China.
  • 3 State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China.
  • 4 Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China; Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing 100005, China.
  • 5 Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
  • 6 Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
  • 7 Syngenta, Jealott's Hill International Research Centre, Bracknell, Berkshire RG42 6EY, UK.
  • 8 Department of Biophysics, School of Basic Medical Sciences, Peking University, Beijing 100191, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China. Electronic address: lbai@pku.edu.cn.
PMID: 40413744 DOI: 10.1016/j.celrep.2025.115753
Abstract

The Fungal plasma membrane H+-ATPase Pma1 hydrolyzes ATP to pump protons out of the cell to maintain the intracellular pH and membrane potential. Pma1 is unique among the P-type ATPases as it functions as a hexamer, although the underlying mechanism has been unclear. Here, we show that the Pma1 hexamer functions cooperatively, and the cooperativity is mediated by the domain-swapped N-terminal extension (NTE). The NTE of one Pma1 subunit binds to the nucleotide-binding domain of a neighboring subunit and, thus, couples the conformational changes of two neighboring subunits, enabling inter-subunit cooperativity of the ATPase activity by the hexamer. We further demonstrate that the NTE is essential for Pma1's cooperative activity and physiological function. Therefore, our work suggests that Pma1 assembles a hexamer to promote a more efficient proton-pumping activity, perhaps to rapidly respond to environmental changes, and may facilitate Antifungal drug development targeting Pma1.

Keywords

CP: Molecular biology; cooperative mechanism; fungi; hexamer; plasma membrane H+-ATPase; structure.

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