2. Academic Validation
  3. Structure of the human ATP synthase

Structure of the human ATP synthase

  • Mol Cell. 2023 May 19;S1097-2765(23)00324-6. doi: 10.1016/j.molcel.2023.04.029.
Yuezheng Lai 1,  Yuying Zhang 1,  Shan Zhou 2,  Jinxu Xu 1,  Zhanqiang Du 1,  Ziyan Feng 1,  Long Yu 1,  Ziqing Zhao 1,  Weiwei Wang 3,  Yanting Tang 4,  Xiuna Yang 3,  Luke W Guddat 5,  Fengjiang Liu 6,  Yan Gao 7,  Zihe Rao 8,  Hongri Gong 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Medicinal Chemical Biology and Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China; Institute for Immunology, College of Life Sciences, Nankai University, Tianjin 300071, China.
  • 2 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300350, China.
  • 3 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 4 State Key Laboratory of Medicinal Chemical Biology and Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China.
  • 5 School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
  • 6 Innovative Center for Pathogen Research, Guangzhou Laboratory, Guangzhou 510005, China. Electronic address: [email protected].
  • 7 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: [email protected].
  • 8 State Key Laboratory of Medicinal Chemical Biology and Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China; State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300350, China; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Innovative Center for Pathogen Research, Guangzhou Laboratory, Guangzhou 510005, China; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences (CAS), Beijing 100101, China; Laboratory of Structural Biology, Tsinghua University, Beijing 100084, China. Electronic address: [email protected].
  • 9 State Key Laboratory of Medicinal Chemical Biology and Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China; Institute for Immunology, College of Life Sciences, Nankai University, Tianjin 300071, China. Electronic address: [email protected].
PMID: 37244256 DOI: 10.1016/j.molcel.2023.04.029
Abstract

Biological energy currency ATP is produced by F1Fo-ATP synthase. However, the molecular mechanism for human ATP Synthase action remains unknown. Here, we present snapshot images for three main rotational states and one substate of human ATP Synthase using cryoelectron microscopy. These structures reveal that the release of ADP occurs when the β subunit of F1Fo-ATP synthase is in the open conformation, showing how ADP binding is coordinated during synthesis. The accommodation of the symmetry mismatch between F1 and Fo motors is resolved by the torsional flexing of the entire complex, especially the γ subunit, and the rotational substep of the c subunit. Water molecules are identified in the inlet and outlet half-channels, suggesting that the proton transfer in these two half-channels proceed via a Grotthus mechanism. Clinically relevant mutations are mapped to the structure, showing that they are mainly located at the subunit-subunit interfaces, thus causing instability of the complex.

Keywords

ATP synthase disease; Grotthus mechanism; cryoelectron microscopy; human ATP synthase; proton translocation; symmetry mismatch.

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