2. Academic Validation
  3. Engineering of a mammalian VMAT2 for cryo-EM analysis results in non-canonical protein folding

Engineering of a mammalian VMAT2 for cryo-EM analysis results in non-canonical protein folding

  • Nat Commun. 2024 Aug 2;15(1):6511. doi: 10.1038/s41467-024-50934-5.
Ying Lyu # 1,  Chunting Fu # 1,  Haiyun Ma # 2,  Zhaoming Su 3,  Ziyi Sun 4,  Xiaoming Zhou 5
Affiliations

Affiliations

  • 1 Department of Integrated Traditional Chinese and Western Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
  • 2 State Key Laboratory of Biotherapy, Department of Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
  • 3 State Key Laboratory of Biotherapy, Department of Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China. zsu@wchscu.cn.
  • 4 Department of Integrated Traditional Chinese and Western Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China. ziyi.sun@scu.edu.cn.
  • 5 Department of Integrated Traditional Chinese and Western Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China. x.zhou@scu.edu.cn.
  • # Contributed equally.
PMID: 39095428 DOI: 10.1038/s41467-024-50934-5
Abstract

Vesicular Monoamine Transporter 2 (VMAT2) belongs to the major facilitator superfamily (MFS), and mediates cytoplasmic monoamine packaging into presynaptic vesicles. Here, we present two cryo-EM structures of VMAT2, with a frog VMAT2 adopting a canonical MFS fold and an engineered sheep VMAT2 adopting a non-canonical fold. Both VMAT2 proteins mediate uptake of a selective fluorescent VMAT2 substrate into cells. Molecular docking, substrate binding and transport analysis reveal potential substrate binding mechanism in VMAT2. Meanwhile, caution is advised when interpreting engineered membrane protein structures.

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