Aaron T. Bozzi, Lukas B. Bane, Wilhelm A. Weihofen, Abhishek Singharoy,
Eduardo R. Guillen, Hidde L. Ploegh, Klaus Schulten, and Rachelle Gaudet.
Crystal structure and conformational change mechanism of a bacterial
Nramp-family divalent metal transporter.
Structure, 24:2102-2114, 2016.
(PMC: PMC5143219)
BOZZ2016A
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-toarginine
mutations, which 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.
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