Conserved methionine dictates substrate preference in Nramp-family divalent metal transporters

Aaron T. Bozzi, Lukas B. Bane, Wilhelm A. Weihofen, Anne L. McCabe, Abhishek Singharoy, Christophe J. Chipot, Klaus Schulten, Rachelle Gaudet

Research output: Contribution to journalArticlepeer-review

55 Scopus citations


Natural resistance-associated macrophage protein (Nramp) family transporters catalyze uptake of essential divalent transition metals like iron and manganese. To discriminate against abundant competitors, the Nramp metal-binding site should favor softer transition metals, which interact either covalently or ionically with coordinating molecules, over hard calcium and magnesium, which interact mainly ionically. The metal-binding site contains an unusual, but conserved, methionine, and its sulfur coordinates transition metal substrates, suggesting a vital role in their transport. Using a bacterial Nramp model system, we show that, surprisingly, this conserved methionine is dispensable for transport of the physiological manganese substrate and similar divalents iron and cobalt, with several small amino acid replacements still enabling robust uptake. Moreover, the methionine sulfur's presence makes the toxic metal cadmium a preferred substrate. However, a methionine-to-alanine substitution enables transport of calcium and magnesium. Thus, the putative evolutionary pressure to maintain the Nramp metal-binding methionine likely exists because it-more effectively than any other amino acid-increases selectivity for low-abundance transition metal transport in the presence of high-abundance divalents like calcium and magnesium.

Original languageEnglish (US)
Pages (from-to)10310-10315
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number37
StatePublished - Sep 13 2016
Externally publishedYes


  • Divalent metal transporter dmt1
  • Hard-soft acid-base theory
  • Ion selectivity filters
  • MntH
  • Transition metals

ASJC Scopus subject areas

  • General


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