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 journalArticle

13 Citations (Scopus)

Abstract

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
Volume113
Issue number37
DOIs
StatePublished - Sep 13 2016
Externally publishedYes

Fingerprint

Methionine
Metals
Magnesium
Manganese
Calcium
Sulfur
Protein Binding
Iron
Binding Sites
Amino Acids
natural resistance-associated macrophage protein 1
Poisons
Cobalt
Cadmium
Alanine
Pressure

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Conserved methionine dictates substrate preference in Nramp-family divalent metal transporters. / Bozzi, Aaron T.; Bane, Lukas B.; Weihofen, Wilhelm A.; McCabe, Anne L.; Singharoy, Abhishek; Chipot, Christophe J.; Schulten, Klaus; Gaudet, Rachelle.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 37, 13.09.2016, p. 10310-10315.

Research output: Contribution to journalArticle

Bozzi, Aaron T. ; Bane, Lukas B. ; Weihofen, Wilhelm A. ; McCabe, Anne L. ; Singharoy, Abhishek ; Chipot, Christophe J. ; Schulten, Klaus ; Gaudet, Rachelle. / Conserved methionine dictates substrate preference in Nramp-family divalent metal transporters. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 37. pp. 10310-10315.
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