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

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  • Wout Oosterheert

    (Utrecht University)

  • Laura S. Bezouwen

    (Utrecht University
    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)

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.

Suggested Citation

  • Wout Oosterheert & Laura S. Bezouwen & Remco N. P. Rodenburg & Joke Granneman & Friedrich Förster & Andrea Mattevi & Piet Gros, 2018. "Cryo-EM structures of human STEAP4 reveal mechanism of iron(III) reduction," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06817-7
    DOI: 10.1038/s41467-018-06817-7
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