| Structural highlights
6hd1 is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | 44E, FAD, HEM, NAG, NAP |
| Related: | 6hcy |
| Gene: | STEAP4, STAMP2, TNFAIP9 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[STEA4_HUMAN] Metalloreductase that has the ability to reduce both Fe(3+) to Fe(2+) and Cu(2+) to Cu(1+) (By similarity). Uses NADP(+) as acceptor (By similarity). Plays a role in systemic metabolic homeostasis, integrating inflammatory and metabolic responses (By similarity). Associated with obesity and insulin-resistance (PubMed:18430367, PubMed:18381574). Involved in inflammatory arthritis, through the regulation of inflammatory cytokines (PubMed:19660107). Inhibits anchorage-independent cell proliferation (PubMed:19787193).[1] [2] [3] [4]
Publication Abstract from PubMed
Enzymes of the six-transmembrane epithelial antigen of the prostate (STEAP) family reduce Fe(3+) and Cu(2+) 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 Fe(3+)-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.
Cryo-EM structures of human STEAP4 reveal mechanism of iron(III) reduction.,Oosterheert W, van Bezouwen LS, Rodenburg RNP, Granneman J, Forster F, Mattevi A, Gros P Nat Commun. 2018 Oct 18;9(1):4337. doi: 10.1038/s41467-018-06817-7. PMID:30337524[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Arner P, Stenson BM, Dungner E, Naslund E, Hoffstedt J, Ryden M, Dahlman I. Expression of six transmembrane protein of prostate 2 in human adipose tissue associates with adiposity and insulin resistance. J Clin Endocrinol Metab. 2008 Jun;93(6):2249-54. doi: 10.1210/jc.2008-0206. Epub , 2008 Apr 1. PMID:18381574 doi:https://dx.doi.org/10.1210/jc.2008-0206
- ↑ Zhang CM, Chi X, Wang B, Zhang M, Ni YH, Chen RH, Li XN, Guo XR. Downregulation of STEAP4, a highly-expressed TNF-alpha-inducible gene in adipose tissue, is associated with obesity in humans. Acta Pharmacol Sin. 2008 May;29(5):587-92. doi: 10.1111/j.1745-7254.2008.00793.x. PMID:18430367 doi:https://dx.doi.org/10.1111/j.1745-7254.2008.00793.x
- ↑ Inoue A, Matsumoto I, Tanaka Y, Iwanami K, Kanamori A, Ochiai N, Goto D, Ito S, Sumida T. Tumor necrosis factor alpha-induced adipose-related protein expression in experimental arthritis and in rheumatoid arthritis. Arthritis Res Ther. 2009;11(4):R118. doi: 10.1186/ar2779. Epub 2009 Aug 6. PMID:19660107 doi:https://dx.doi.org/10.1186/ar2779
- ↑ Tamura T, Chiba J. STEAP4 regulates focal adhesion kinase activation and CpG motifs within STEAP4 promoter region are frequently methylated in DU145, human androgen-independent prostate cancer cells. Int J Mol Med. 2009 Nov;24(5):599-604. PMID:19787193
- ↑ Oosterheert W, van Bezouwen LS, Rodenburg RNP, Granneman J, Forster F, Mattevi A, Gros P. 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. PMID:30337524 doi:https://dx.doi.org/10.1038/s41467-018-06817-7
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