STEA4_RAT
ID STEA4_RAT Reviewed; 470 AA.
AC Q4V8K1;
DT 01-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2005, sequence version 1.
DT 03-AUG-2022, entry version 113.
DE RecName: Full=Metalloreductase STEAP4;
DE EC=1.16.1.9 {ECO:0000269|PubMed:23733181};
DE AltName: Full=Six-transmembrane epithelial antigen of prostate 4;
GN Name=Steap4;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Thymus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [2]
RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 1-195 IN COMPLEX WITH NADP,
RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP MUTAGENESIS OF LEU-194; LEU-196 AND TRP-200.
RX PubMed=23733181; DOI=10.1074/jbc.m113.479154;
RA Gauss G.H., Kleven M.D., Sendamarai A.K., Fleming M.D., Lawrence C.M.;
RT "The crystal structure of six-transmembrane epithelial antigen of the
RT prostate 4 (Steap4), a ferri/cuprireductase, suggests a novel interdomain
RT flavin-binding site.";
RL J. Biol. Chem. 288:20668-20682(2013).
CC -!- FUNCTION: Integral membrane protein that functions as NADPH-dependent
CC ferric-chelate reductase, using NADPH from one side of the membrane to
CC reduce a Fe(3+) chelate that is bound on the other side of the
CC membrane. Mediates sequential transmembrane electron transfer from
CC NADPH to FAD and onto heme, and finally to the Fe(3+) chelate
CC (PubMed:23733181). Can also reduce Cu(2+) to Cu(1+) (PubMed:23733181).
CC Plays a role in systemic metabolic homeostasis, integrating
CC inflammatory and metabolic responses (By similarity). Associated with
CC obesity and insulin-resistance (By similarity). Involved in
CC inflammatory arthritis, through the regulation of inflammatory
CC cytokines (By similarity). Inhibits anchorage-independent cell
CC proliferation (By similarity). {ECO:0000250|UniProtKB:Q687X5,
CC ECO:0000250|UniProtKB:Q923B6, ECO:0000269|PubMed:23733181}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 a Fe(II)-siderophore + H(+) + NADP(+) = 2 a Fe(III)-
CC siderophore + NADPH; Xref=Rhea:RHEA:28795, Rhea:RHEA-COMP:11342,
CC Rhea:RHEA-COMP:11344, ChEBI:CHEBI:15378, ChEBI:CHEBI:29033,
CC ChEBI:CHEBI:29034, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.16.1.9;
CC Evidence={ECO:0000269|PubMed:23733181};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000269|PubMed:23733181};
CC Note=Can also utilize the flavins FMN and riboflavin.
CC {ECO:0000269|PubMed:23733181};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:Q687X5};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=4.8 uM for Fe(3+)-NTA {ECO:0000269|PubMed:23733181};
CC KM=6.8 uM for Fe(3+)-citrate {ECO:0000269|PubMed:23733181};
CC KM=11.2 uM for Cu(2+)-NTA {ECO:0000269|PubMed:23733181};
CC KM=9.9 uM for Cu(2+)-histidine {ECO:0000269|PubMed:23733181};
CC pH dependence:
CC Optimum pH is 5-7. At higher pH levels, ferric reductase activity
CC rapidly declines while cupric reductase activity remains high.
CC {ECO:0000269|PubMed:23733181};
CC -!- SUBUNIT: Homotrimer. Interacts with PTK2/FAK1; the interaction may
CC regulate PTK2 phosphorylation. {ECO:0000250|UniProtKB:Q687X5}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:23733181};
CC Multi-pass membrane protein {ECO:0000250|UniProtKB:Q687X5}. Golgi
CC apparatus membrane {ECO:0000250|UniProtKB:Q687X5}; Multi-pass membrane
CC protein {ECO:0000250|UniProtKB:Q687X5}. Early endosome membrane
CC {ECO:0000250|UniProtKB:Q687X5}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q687X5}.
CC -!- SIMILARITY: Belongs to the STEAP family. {ECO:0000305}.
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DR EMBL; BC097353; AAH97353.1; -; mRNA.
DR RefSeq; NP_001037730.1; NM_001044265.1.
DR PDB; 2YJZ; X-ray; 2.20 A; A/B/C/D=1-195.
DR PDBsum; 2YJZ; -.
DR AlphaFoldDB; Q4V8K1; -.
DR SMR; Q4V8K1; -.
DR STRING; 10116.ENSRNOP00000011432; -.
DR PhosphoSitePlus; Q4V8K1; -.
DR PaxDb; Q4V8K1; -.
DR PRIDE; Q4V8K1; -.
DR Ensembl; ENSRNOT00000011432; ENSRNOP00000011432; ENSRNOG00000008602.
DR GeneID; 499991; -.
DR KEGG; rno:499991; -.
DR UCSC; RGD:1560331; rat.
DR CTD; 79689; -.
DR RGD; 1560331; Steap4.
DR eggNOG; ENOG502R746; Eukaryota.
DR GeneTree; ENSGT00390000008042; -.
DR InParanoid; Q4V8K1; -.
DR OMA; GWERNPK; -.
DR OrthoDB; 638341at2759; -.
DR PhylomeDB; Q4V8K1; -.
DR PRO; PR:Q4V8K1; -.
DR Proteomes; UP000002494; Chromosome 4.
DR Bgee; ENSRNOG00000008602; Expressed in liver and 17 other tissues.
DR ExpressionAtlas; Q4V8K1; baseline and differential.
DR Genevisible; Q4V8K1; RN.
DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005768; C:endosome; ISO:RGD.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; ISO:RGD.
DR GO; GO:0005654; C:nucleoplasm; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0008823; F:cupric reductase activity; ISO:RGD.
DR GO; GO:0009055; F:electron transfer activity; ISO:RGD.
DR GO; GO:0071949; F:FAD binding; ISO:RGD.
DR GO; GO:0052851; F:ferric-chelate reductase (NADPH) activity; ISO:RGD.
DR GO; GO:0020037; F:heme binding; ISO:RGD.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0015677; P:copper ion import; ISO:RGD.
DR GO; GO:0045444; P:fat cell differentiation; ISS:UniProtKB.
DR GO; GO:0033212; P:iron import into cell; ISO:RGD.
DR GO; GO:0070207; P:protein homotrimerization; ISO:RGD.
DR DisProt; DP02980; -.
DR InterPro; IPR013130; Fe3_Rdtase_TM_dom.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR028939; P5C_Rdtase_cat_N.
DR Pfam; PF03807; F420_oxidored; 1.
DR Pfam; PF01794; Ferric_reduct; 1.
DR SUPFAM; SSF51735; SSF51735; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Copper; Endosome; FAD; Flavoprotein;
KW Golgi apparatus; Heme; Ion transport; Iron; Iron transport; Membrane;
KW Metal-binding; Oxidoreductase; Reference proteome; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1..470
FT /note="Metalloreductase STEAP4"
FT /id="PRO_0000285176"
FT TRANSMEM 202..224
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q687X5"
FT TRANSMEM 236..256
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q687X5"
FT TRANSMEM 293..313
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q687X5"
FT TRANSMEM 342..362
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q687X5"
FT TRANSMEM 381..401
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q687X5"
FT TRANSMEM 419..439
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q687X5"
FT DOMAIN 249..391
FT /note="Ferric oxidoreductase"
FT /evidence="ECO:0000255"
FT BINDING 27..30
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:23733181,
FT ECO:0007744|PDB:2YJZ"
FT BINDING 49..50
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:23733181,
FT ECO:0007744|PDB:2YJZ"
FT BINDING 67
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:23733181,
FT ECO:0007744|PDB:2YJZ"
FT BINDING 81..85
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:23733181,
FT ECO:0007744|PDB:2YJZ"
FT BINDING 106
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:23733181,
FT ECO:0007744|PDB:2YJZ"
FT BINDING 139
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:23733181,
FT ECO:0007744|PDB:2YJZ"
FT BINDING 140
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q687X5"
FT BINDING 148
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q687X5"
FT BINDING 171
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:23733181,
FT ECO:0007744|PDB:2YJZ"
FT BINDING 269
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q687X5"
FT BINDING 290
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q687X5"
FT BINDING 304
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000250|UniProtKB:P32791"
FT BINDING 366
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q687X5"
FT BINDING 383
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q687X5"
FT BINDING 397
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000250|UniProtKB:P32791"
FT MUTAGEN 194
FT /note="L->A: No significant effect on enzyme activity or
FT subcellular location."
FT /evidence="ECO:0000269|PubMed:23733181"
FT MUTAGEN 196
FT /note="L->A: No significant effect on enzyme activity or
FT subcellular location."
FT /evidence="ECO:0000269|PubMed:23733181"
FT MUTAGEN 200
FT /note="W->A: No significant effect on enzyme activity or
FT subcellular location."
FT /evidence="ECO:0000269|PubMed:23733181"
FT STRAND 21..25
FT /evidence="ECO:0007829|PDB:2YJZ"
FT HELIX 29..40
FT /evidence="ECO:0007829|PDB:2YJZ"
FT STRAND 44..50
FT /evidence="ECO:0007829|PDB:2YJZ"
FT STRAND 62..66
FT /evidence="ECO:0007829|PDB:2YJZ"
FT HELIX 67..72
FT /evidence="ECO:0007829|PDB:2YJZ"
FT STRAND 75..79
FT /evidence="ECO:0007829|PDB:2YJZ"
FT HELIX 83..85
FT /evidence="ECO:0007829|PDB:2YJZ"
FT HELIX 87..96
FT /evidence="ECO:0007829|PDB:2YJZ"
FT STRAND 100..103
FT /evidence="ECO:0007829|PDB:2YJZ"
FT STRAND 112..115
FT /evidence="ECO:0007829|PDB:2YJZ"
FT HELIX 117..124
FT /evidence="ECO:0007829|PDB:2YJZ"
FT STRAND 128..132
FT /evidence="ECO:0007829|PDB:2YJZ"
FT HELIX 141..144
FT /evidence="ECO:0007829|PDB:2YJZ"
FT STRAND 152..158
FT /evidence="ECO:0007829|PDB:2YJZ"
FT HELIX 160..172
FT /evidence="ECO:0007829|PDB:2YJZ"
FT STRAND 176..179
FT /evidence="ECO:0007829|PDB:2YJZ"
FT HELIX 183..185
FT /evidence="ECO:0007829|PDB:2YJZ"
FT HELIX 186..191
FT /evidence="ECO:0007829|PDB:2YJZ"
FT HELIX 192..194
FT /evidence="ECO:0007829|PDB:2YJZ"
SQ SEQUENCE 470 AA; 52765 MW; C2323082CB3B6465 CRC64;
MEKTCADEFP LTVDSSEKQG VVCIFGTGDF GKSLGLKMLQ CGYSVVFGSR NPQVSSLLPR
GAEVLCYSEA ASRSDVIVLA VHREHYDFLA ELADSLKGRV LIDVSNNQKM NQYPESNAEY
LAQLVPGAHV VKAFNTISAW ALQSGTLDAS RQVFVCGNDS KAKDRVMDIA RTLGLTPLDQ
GSLVAAKEIE NYPLQLFPMW RFPFYLSSGL CVFFFVYCAI REVIYPYVTG KTDSTYRLVV
SIPNRVFPIT ALTLLALVYL PGILAAILQL YRGTKYRRFP NWLDHWMLCR KQLGLVALGF
AFLHAIYTLV IPIRYYVRWR LRNATITQAL TNKDSPFSSS TAWLSDSYLA LGILGFFLFL
LLGITSLPSV SNMVNWREFR FVQSKLGYLT LVLCTAHTLV YGGKRFLSPS ILIWSLPSAY
ILALIIPCTV LVMKFILIMP CIDKTLTRIR QGWERKSKYA QSTLNGKSDI
