Cooperative transport mechanism of human monocarboxylate transporter 2

Bo Zhang, Qiuheng Jin, Lizhen Xu, Ningning Li, Ying Meng, Shenghai Chang, Xiang Zheng, Jiangqin Wang, Yuan Chen, Dante Neculai, Ning Gao, Xiaokang Zhang (), Fan Yang (), Jiangtao Guo () and Sheng Ye ()
Additional contact information
Bo Zhang: Zhejiang University
Qiuheng Jin: Zhejiang University
Lizhen Xu: First Affiliated Hospital, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine
Ningning Li: Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Peking University
Ying Meng: School of Basic Medical Sciences, Zhejiang University
Shenghai Chang: Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine
Xiang Zheng: Zhejiang A & F University
Jiangqin Wang: Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine
Yuan Chen: Zhejiang A & F University
Dante Neculai: School of Basic Medical Sciences, Zhejiang University
Ning Gao: Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Peking University
Xiaokang Zhang: School of Life Sciences, Tianjin University
Fan Yang: First Affiliated Hospital, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine
Jiangtao Guo: Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine
Sheng Ye: Zhejiang University

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16334-1

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