Aaron T. Bozzi, Lukas B. Bane, Wilhelm Weihofen, Anne McCabe, Abhishek
Singharoy, Chris Chipot, Klaus Schulten, and Rachelle Gaudet.
Conserved methionine dictates substrate preference in Nramp-family
divalent metal transporters.
Proceedings of the National Academy of Sciences, USA,
113:10310-10315, 2016.
(PMC: PMC5027461)
BOZZ2016
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.
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