TCB Publications - Abstract

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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