Cell Research, 22 May, 2024, DOI：https://doi.org/10.1038/s41422-024-00974-9

Structural snapshots of human VMAT2 reveal insights into substrate recognition and proton coupling mechanism

Di Wu, Zhuoya Yu, Qihao Chen, Jun Zhao, Bo Huang, Yuhang Wang, Jiawei Su, Na Li, Daohua Jiang & Yan Zhao

Abstract

Monoamine neurotransmitters include indolamine serotonin (5-HT), the catecholamine dopamine (DA), epinephrine (EP), norepinephrine (NE), and imidazolamine histamine (HA). These neurotransmitters are critical in emotion, arousal, mood, reward, sleep, and memory. VMAT2 accumulates monoamine neurotransmitters into synaptic vesicles for storage and eventual exocytotic release. Recent studies have shed light on the recognition mechanisms of 5-HT and VMAT2 inhibitors. However, it is not yet fully understood how VMAT2 recognizes these chemically diverse neurotransmitters, as well as a parkinsonism-inducer MPP⁺, and demonstrates comparable transport activities. Especially, the histamine is thought to bind to a different site. Moreover, the uptake activity of VMAT2 is driven by the transmembrane proton electrochemical gradient generated by vacuolar H⁺-ATPase. However, based on the current structures of VMAT2 bound to 5-HT, the protonation sites involved in substrate binding differ and are recognized either as E312 or D399. The binding poses of 5-HT within VMAT2, in both inward-facing and outward-facing conformations, are dramatically different, with the amine group undergoing a 180-degree flip from the cytosol side to the lumen side. Therefore, the substrate binding poses in different functional states and the exact protonation site require further clarification. In addition, another protonation site governing the conformational transition remains undefined.

Article link：https://www.nature.com/articles/s41422-024-00974-9