Malinauskaite Lina, Quick Matthias, Reinhard Linda, Lyons Joseph A, Yano Hideaki, Javitch Jonathan A, Nissen Poul
1] Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Aarhus University, Aarhus, Denmark. [2] Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
1] Center for Molecular Recognition, Columbia University College of Physicians and Surgeons, New York, New York, USA. [2] Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York, USA. [3] Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York, USA.
Nat Struct Mol Biol. 2014 Nov;21(11):1006-12. doi: 10.1038/nsmb.2894. Epub 2014 Oct 5.
Neurotransmitter/sodium symporters (NSSs) terminate synaptic signal transmission by Na+-dependent reuptake of released neurotransmitters. Key conformational states have been reported for the bacterial homolog LeuT and an inhibitor-bound Drosophila dopamine transporter. However, a coherent mechanism of Na+-driven transport has not been described. Here, we present two crystal structures of MhsT, an NSS member from Bacillus halodurans, in occluded inward-facing states with bound Na+ ions and L-tryptophan, providing insight into the cytoplasmic release of Na+. The switch from outward- to inward-oriented states is centered on the partial unwinding of transmembrane helix 5, facilitated by a conserved GlyX9Pro motif that opens an intracellular pathway for water to access the Na2 site. We propose a mechanism, based on our structural and functional findings, in which solvation through the TM5 pathway facilitates Na+ release from Na2 and the transition to an inward-open state.
神经递质/钠同向转运体（NSSs）通过对释放的神经递质进行钠离子依赖性重摄取来终止突触信号传递。已报道了细菌同源物亮氨酸转运蛋白（LeuT）和一种与抑制剂结合的果蝇多巴胺转运体的关键构象状态。然而，尚未描述钠离子驱动转运的连贯机制。在此，我们展示了嗜碱芽孢杆菌NSS成员MhsT的两个晶体结构，其处于向内封闭状态，结合有钠离子和L-色氨酸，这为钠离子的胞质释放提供了见解。从向外状态到向内状态的转变以跨膜螺旋5的部分解旋为中心，由保守的GlyX9Pro基序促进，该基序打开了一条细胞内通道，使水能够进入Na2位点。基于我们的结构和功能发现，我们提出了一种机制，其中通过跨膜螺旋5途径的溶剂化作用促进了钠离子从Na2的释放以及向内开放状态的转变。
