Cooperative transport mechanism of human monocarboxylate transporter 2.
Bo ZhangQiuheng JinLizhen XuNing-Ning LiYing MengShenghai ChangXiang ZhengJiangqin WangYuan ChenDante NeculaiNing GaoXiaokang ZhangFan YangJiang Tao GuoSheng YePublished in: Nature communications (2020)
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.
Keyphrases
- endothelial cells
- induced apoptosis
- electron microscopy
- induced pluripotent stem cells
- pluripotent stem cells
- high resolution
- oxidative stress
- machine learning
- gene expression
- deep learning
- cell proliferation
- multidrug resistant
- sensitive detection
- gram negative
- protein protein
- single molecule
- reactive oxygen species