2. Academic Validation
  3. Cryo-EM structures of human STEAP4 reveal mechanism of iron(III) reduction

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

  • Nat Commun. 2018 Oct 18;9(1):4337. doi: 10.1038/s41467-018-06817-7.
Wout Oosterheert 1,  Laura S van Bezouwen 1 2,  Remco N P Rodenburg 1,  Joke Granneman 1,  Friedrich Förster 2,  Andrea Mattevi 3,  Piet Gros 4
Affiliations

Affiliations

  • 1 Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands.
  • 2 Cryo-Electron Microscopy, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands.
  • 3 Department of Biology and Biotechnology 'L. Spallanzani', University of Pavia, 27100, Pavia, Italy.
  • 4 Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands. [email protected].
PMID: 30337524 DOI: 10.1038/s41467-018-06817-7
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.

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