Crystal Structure and Conformational Change Mechanism of a Bacterial Nramp-Family Divalent Metal Transporter

Aaron T. Bozzi, Lukas B. Bane, Wilhelm A. Weihofen, Abhishek Singharoy, Eduardo R. Guillen, Hidde L. Ploegh, Klaus Schulten, Rachelle Gaudet

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

The widely conserved natural resistance-associated macrophage protein (Nramp) family of divalent metal transporters enables manganese import in bacteria and dietary iron uptake in mammals. We determined the crystal structure of the Deinococcus radiodurans Nramp homolog (DraNramp) in an inward-facing apo state, including the complete transmembrane (TM) segment 1a (absent from a previous Nramp structure). Mapping our cysteine accessibility scanning results onto this structure, we identified the metal-permeation pathway in the alternate outward-open conformation. We investigated the functional impact of two natural anemia-causing glycine-to-arginine mutations that impaired transition metal transport in both human Nramp2 and DraNramp. The TM4 G153R mutation perturbs the closing of the outward metal-permeation pathway and alters the selectivity of the conserved metal-binding site. In contrast, the TM1a G45R mutation prevents conformational change by sterically blocking the essential movement of that helix, thus locking the transporter in an inward-facing state.

Original languageEnglish (US)
Pages (from-to)2102-2114
Number of pages13
JournalStructure
Volume24
Issue number12
DOIs
StatePublished - Dec 6 2016

Keywords

  • LeuT fold
  • MntH
  • Nramp
  • crystallography
  • cysteine accessibility
  • divalent metal transporter
  • microcytic anemia
  • natural resistance-associated macrophage protein
  • transition metals

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Bozzi, A. T., Bane, L. B., Weihofen, W. A., Singharoy, A., Guillen, E. R., Ploegh, H. L., Schulten, K., & Gaudet, R. (2016). Crystal Structure and Conformational Change Mechanism of a Bacterial Nramp-Family Divalent Metal Transporter. Structure, 24(12), 2102-2114. https://doi.org/10.1016/j.str.2016.09.017