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| | ==human STEAP4 bound to NADP, FAD, heme and Fe(III)-NTA.== | | ==human STEAP4 bound to NADP, FAD, heme and Fe(III)-NTA.== |
| - | <StructureSection load='6hcy' size='340' side='right'caption='[[6hcy]], [[Resolution|resolution]] 3.10Å' scene=''> | + | <SX load='6hcy' size='340' side='right' viewer='molstar' caption='[[6hcy]], [[Resolution|resolution]] 3.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6hcy]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HCY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HCY FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6hcy]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HCY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6HCY FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=44E:(2R)-3-(PHOSPHONOOXY)PROPANE-1,2-DIYL+DIHEXANOATE'>44E</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.1Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">STEAP4, STAMP2, TNFAIP9 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=44E:(2R)-3-(PHOSPHONOOXY)PROPANE-1,2-DIYL+DIHEXANOATE'>44E</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6hcy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hcy OCA], [http://pdbe.org/6hcy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6hcy RCSB], [http://www.ebi.ac.uk/pdbsum/6hcy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6hcy ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6hcy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hcy OCA], [https://pdbe.org/6hcy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6hcy RCSB], [https://www.ebi.ac.uk/pdbsum/6hcy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6hcy ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/STEA4_HUMAN 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).<ref>PMID:18381574</ref> <ref>PMID:18430367</ref> <ref>PMID:19660107</ref> <ref>PMID:19787193</ref> | + | [https://www.uniprot.org/uniprot/STEA4_HUMAN 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).<ref>PMID:18381574</ref> <ref>PMID:18430367</ref> <ref>PMID:19660107</ref> <ref>PMID:19787193</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| - | </StructureSection> | + | </SX> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Bezouwen, L S.van]]
| + | [[Category: Forster F]] |
| - | [[Category: Forster, F]] | + | [[Category: Gros P]] |
| - | [[Category: Gros, P]] | + | [[Category: Mattevi A]] |
| - | [[Category: Mattevi, A]] | + | [[Category: Oosterheert W]] |
| - | [[Category: Oosterheert, W]] | + | [[Category: Rodenburg RNP]] |
| - | [[Category: Rodenburg, R N.P]] | + | [[Category: Van Bezouwen LS]] |
| - | [[Category: Cofactor-binding]] | + | |
| - | [[Category: Electron transfer]]
| + | |
| - | [[Category: Enzyme]]
| + | |
| - | [[Category: Membrane protein]]
| + | |
| - | [[Category: Metalloreductase]]
| + | |
| Structural highlights
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:http://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:http://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:http://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:http://dx.doi.org/10.1038/s41467-018-06817-7
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