Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States.
Elife. 2019 Feb 4;8:e41124. doi: 10.7554/eLife.41124.
Nramp family transporters-expressed in organisms from bacteria to humans-enable uptake of essential divalent transition metals via an alternating-access mechanism that also involves proton transport. We present high-resolution structures of (Dra)Nramp in multiple conformations to provide a thorough description of the Nramp transport cycle by identifying the key intramolecular rearrangements and changes to the metal coordination sphere. Strikingly, while metal transport requires cycling from outward- to inward-open states, efficient proton transport still occurs in outward-locked (but not inward-locked) DraNramp. We propose a model in which metal and proton enter the transporter via the same external pathway to the binding site, but follow separate routes to the cytoplasm, which could facilitate the co-transport of two cationic species. Our results illustrate the flexibility of the LeuT fold to support a broad range of substrate transport and conformational change mechanisms.
Nramp 家族转运蛋白——从细菌到人类的生物体中均有表达——通过涉及质子转运的交替存取机制，使必需的二价过渡金属得以摄取。我们呈现了多个构象的 （Dra）Nramp 的高分辨率结构，通过确定关键的分子内重排和金属配位球的变化，全面描述了 Nramp 转运循环。引人注目的是，尽管金属转运需要从外向开放状态循环到内向开放状态，但在向外锁定（而非向内锁定）的 DraNramp 中仍能有效进行质子转运。我们提出了一个模型，其中金属和质子通过相同的外部途径进入转运蛋白的结合位点，但沿着不同的路径进入细胞质，这可能有助于两种阳离子物质的共转运。我们的结果说明了 LeuT 折叠的灵活性，能够支持广泛的底物转运和构象变化机制。
