Cryo-EM structures of human STEAP4 reveal mechanism of iron(III) reduction

Wout Oosterheert, Laura S. Bezouwen, Remco N. P. Rodenburg, Joke Granneman, Friedrich Förster, Andrea Mattevi and Piet Gros ()
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Wout Oosterheert: Utrecht University
Laura S. Bezouwen: Utrecht University
Remco N. P. Rodenburg: Utrecht University
Joke Granneman: Utrecht University
Friedrich Förster: Utrecht University
Andrea Mattevi: University of Pavia
Piet Gros: Utrecht University

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: Abstract Enzymes of the six-transmembrane epithelial antigen of the prostate (STEAP) family reduce Fe3+ and Cu2+ ions to facilitate metal-ion uptake by mammalian cells. STEAPs are highly upregulated in several types of cancer, making them potential therapeutic targets. However, the structural basis for STEAP-catalyzed electron transfer through an array of cofactors to metals at the membrane luminal side remains elusive. Here, we report cryo-electron microscopy structures of human STEAP4 in absence and presence of Fe3+-NTA. Domain-swapped, trimeric STEAP4 orients NADPH bound to a cytosolic domain onto axially aligned flavin-adenine dinucleotide (FAD) and a single b-type heme that cross the transmembrane-domain to enable electron transfer. Substrate binding within a positively charged ring indicates that iron gets reduced while in complex with its chelator. These molecular principles of iron reduction provide a basis for exploring STEAPs as therapeutic targets.

Date: 2018
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DOI: 10.1038/s41467-018-06817-7

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