2. Academic Validation
  3. Cooperative transport mechanism of human monocarboxylate transporter 2

Cooperative transport mechanism of human monocarboxylate transporter 2

  • Nat Commun. 2020 May 15;11(1):2429. doi: 10.1038/s41467-020-16334-1.
Bo Zhang  # 1,  Qiuheng Jin  # 1,  Lizhen Xu  # 2,  Ningning Li  # 3,  Ying Meng 4,  Shenghai Chang 5 6,  Xiang Zheng 7,  Jiangqin Wang 5 8,  Yuan Chen 7,  Dante Neculai 4,  Ning Gao 3,  Xiaokang Zhang 9,  Fan Yang 10,  Jiangtao Guo 11 12,  Sheng Ye 13 14
Affiliations

Affiliations

  • 1 Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China.
  • 2 Department of Biophysics and Kidney Disease Center, First Affiliated Hospital, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 3 State Key Laboratory of Membrane Biology, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Peking University, Beijing, China.
  • 4 Department of Cell Biology, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
  • 5 Department of Biophysics, Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 6 Center of Cryo Electron Microscopy, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 7 The State Key Laboratory of Subtropical Silviculture, Zhejiang A & F University, 666 Wusu street, Lin'an, 311300, China.
  • 8 Department of Biophysics, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 9 Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, China. [email protected].
  • 10 Department of Biophysics and Kidney Disease Center, First Affiliated Hospital, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, 310058, China. [email protected].
  • 11 Department of Biophysics, Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China. [email protected].
  • 12 Department of Biophysics, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, 310058, China. [email protected].
  • 13 Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China. [email protected].
  • 14 Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, China. [email protected].
  • # Contributed equally.
PMID: 32415067 DOI: 10.1038/s41467-020-16334-1
Abstract

Proton-linked monocarboxylate transporters (MCTs) must transport monocarboxylate efficiently to facilitate monocarboxylate efflux in glycolytically active cells, and transport monocarboxylate slowly or even shut down to maintain a physiological monocarboxylate concentration in glycolytically inactive cells. To discover how MCTs solve this fundamental aspect of intracellular monocarboxylate homeostasis in the context of multicellular organisms, we analyzed pyruvate transport activity of human Monocarboxylate Transporter 2 (MCT2). Here we show that MCT2 transport activity exhibits steep dependence on substrate concentration. This property allows MCTs to turn on almost like a switch, which is physiologically crucial to the operation of MCTs in the cellular context. We further determined the cryo-electron microscopy structure of the human MCT2, demonstrating that the concentration sensitivity of MCT2 arises from the strong inter-subunit cooperativity of the MCT2 dimer during transport. These data establish definitively a clear example of evolutionary optimization of protein function.

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