National Institutes of Health/National Institute of Mental Health (NIH/NIMH)
RO1MH63105
米国
引用
ジャーナル: Nature / 年: 2024 タイトル: Structure and topography of the synaptic V-ATPase-synaptophysin complex. 著者: Chuchu Wang / Wenhong Jiang / Jeremy Leitz / Kailu Yang / Luis Esquivies / Xing Wang / Xiaotao Shen / Richard G Held / Daniel J Adams / Tamara Basta / Lucas Hampton / Ruiqi Jian / Lihua Jiang ...著者: Chuchu Wang / Wenhong Jiang / Jeremy Leitz / Kailu Yang / Luis Esquivies / Xing Wang / Xiaotao Shen / Richard G Held / Daniel J Adams / Tamara Basta / Lucas Hampton / Ruiqi Jian / Lihua Jiang / Michael H B Stowell / Wolfgang Baumeister / Qiang Guo / Axel T Brunger / 要旨: Synaptic vesicles are organelles with a precisely defined protein and lipid composition, yet the molecular mechanisms for the biogenesis of synaptic vesicles are mainly unknown. Here we discovered a ...Synaptic vesicles are organelles with a precisely defined protein and lipid composition, yet the molecular mechanisms for the biogenesis of synaptic vesicles are mainly unknown. Here we discovered a well-defined interface between the synaptic vesicle V-ATPase and synaptophysin by in situ cryo-electron tomography and single-particle cryo-electron microscopy of functional synaptic vesicles isolated from mouse brains. The synaptic vesicle V-ATPase is an ATP-dependent proton pump that establishes the proton gradient across the synaptic vesicle, which in turn drives the uptake of neurotransmitters. Synaptophysin and its paralogues synaptoporin and synaptogyrin belong to a family of abundant synaptic vesicle proteins whose function is still unclear. We performed structural and functional studies of synaptophysin-knockout mice, confirming the identity of synaptophysin as an interaction partner with the V-ATPase. Although there is little change in the conformation of the V-ATPase upon interaction with synaptophysin, the presence of synaptophysin in synaptic vesicles profoundly affects the copy number of V-ATPases. This effect on the topography of synaptic vesicles suggests that synaptophysin assists in their biogenesis. In support of this model, we observed that synaptophysin-knockout mice exhibit severe seizure susceptibility, suggesting an imbalance of neurotransmitter release as a physiological consequence of the absence of synaptophysin.