Structures in multiple conformations reveal distinct transition metal and proton pathways in an Nramp transporter
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 Deinococcus radiodurans (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.
Source data for the Nramp sequence alignment have been provided as Figure 2-source data 1. Structural coordinates and structure factors for each crystal structure have been deposited in the PDB under accession codes 6D9W, 6C3I, 6BU5, and 6D91. The unprocessed X-ray diffraction images have been deposited in the SBGrid Data Bank under accession codes 332, 333, 334, 567, 564, and 576. All other data generated or analyzed in this study are included in the manuscript.
Article and author information
National Institute of General Medical Sciences (1R01GM120996)
- Rachelle Gaudet
Jane Coffin Childs Memorial Fund for Medical Research
- Christina M Zimanyi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- José D Faraldo-Gómez, National Heart, Lung and Blood Institute, National Institutes of Health, United States
- Received: August 15, 2018
- Accepted: January 31, 2019
- Accepted Manuscript published: February 4, 2019 (version 1)
- Version of Record published: March 4, 2019 (version 2)
© 2019, Bozzi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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