CYBR1_HUMAN
ID CYBR1_HUMAN Reviewed; 286 AA.
AC Q53TN4; B2RE79; B4DWD7; Q6KC16; Q6KC17; Q6P147; Q6ZR51; Q9H0Q8; Q9H5G5;
DT 15-JAN-2008, integrated into UniProtKB/Swiss-Prot.
DT 24-MAY-2005, sequence version 1.
DT 03-AUG-2022, entry version 145.
DE RecName: Full=Plasma membrane ascorbate-dependent reductase CYBRD1 {ECO:0000305|PubMed:17068337, ECO:0000305|PubMed:30272000};
DE EC=7.2.1.3 {ECO:0000269|PubMed:17068337, ECO:0000269|PubMed:30272000};
DE AltName: Full=Cytochrome b reductase 1 {ECO:0000312|HGNC:HGNC:20797};
DE AltName: Full=Duodenal cytochrome b {ECO:0000303|PubMed:12949720};
DE AltName: Full=Ferric-chelate reductase 3;
GN Name=CYBRD1 {ECO:0000312|HGNC:HGNC:20797};
GN Synonyms=DCYTB {ECO:0000303|PubMed:12949720}, FRRS3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ASN-266.
RC TISSUE=Brain;
RX PubMed=11230166; DOI=10.1101/gr.gr1547r;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J.,
RA Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W.,
RA Ottenwaelder B., Obermaier B., Tampe J., Heubner D., Wambutt R., Korn B.,
RA Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and analysis of
RT 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3), AND VARIANT
RP THR-156.
RC TISSUE=Placenta, Small intestine, Synovium, and Trachea;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ASN-266.
RG NIEHS SNPs program;
RL Submitted (APR-2006) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT ASN-266.
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ASN-266.
RC TISSUE=Skin;
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 [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 65-134 AND 187-285, AND VARIANT
RP HIS-226.
RX PubMed=15338274; DOI=10.1007/s00439-004-1166-y;
RA Zaahl M.G., Merryweather-Clarke A.T., Kotze M.J., van der Merwe S.,
RA Warnich L., Robson K.J.H.;
RT "Analysis of genes implicated in iron regulation in individuals presenting
RT with primary iron overload.";
RL Hum. Genet. 115:409-417(2004).
RN [8]
RP SUBCELLULAR LOCATION, AND INDUCTION.
RX PubMed=12949720; DOI=10.1016/s0016-5085(03)01063-1;
RA Zoller H., Theurl I., Koch R.O., McKie A.T., Vogel W., Weiss G.;
RT "Duodenal cytochrome b and hephaestin expression in patients with iron
RT deficiency and hemochromatosis.";
RL Gastroenterology 125:746-754(2003).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-285, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [11]
RP POLYMORPHISM, AND ROLE IN HEREDITARY HEMOCHROMATOSIS.
RX PubMed=19673882; DOI=10.1111/j.1365-2141.2009.07843.x;
RA Constantine C.C., Anderson G.J., Vulpe C.D., McLaren C.E., Bahlo M.,
RA Yeap H.L., Gertig D.M., Osborne N.J., Bertalli N.A., Beckman K.B., Chen V.,
RA Matak P., McKie A.T., Delatycki M.B., Olynyk J.K., English D.R.,
RA Southey M.C., Giles G.G., Hopper J.L., Allen K.J., Gurrin L.C.;
RT "A novel association between a SNP in CYBRD1 and serum ferritin levels in a
RT cohort study of HFE hereditary haemochromatosis.";
RL Br. J. Haematol. 147:140-149(2009).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-285, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-285, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-232 AND THR-285, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [16]
RP VARIANT HIS-226.
RX PubMed=16521301;
RA Zaahl M.G., Merryweather-Clarke A.T., Kotze M.J., van der Merwe S.,
RA Warnich L., Robson K.J.;
RT "Gene symbol: DCYTB/CYBRD1. Disease: primary iron overload.";
RL Hum. Genet. 118:546-546(2005).
RN [17]
RP ROLE IN HEREDITARY HEMOCHROMATOSIS.
RX PubMed=16521311;
RA Zaahl M.G., Merryweather-Clarke A.T., Kotze M.J., van der Merwe S.,
RA Warnich L., Robson K.J.;
RT "Gene symbol: DCYTB/CYBRD1. Disease: primary iron overload.";
RL Hum. Genet. 118:548-549(2005).
RN [18]
RP ROLE IN HEREDITARY HEMOCHROMATOSIS.
RX PubMed=16521312;
RA Zaahl M.G., Merryweather-Clarke A.T., Kotze M.J., van der Merwe S.,
RA Warnich L., Robson K.J.;
RT "Gene symbol: DCYTB/CYBRD1. Disease: primary iron overload.";
RL Hum. Genet. 118:549-549(2005).
RN [19]
RP INDUCTION.
RX PubMed=17087784; DOI=10.1111/j.1365-2362.2006.01732.x;
RA Li A.C.Y., Warley A., Thoree V., Simpson R.J., McKie A.T., Kodjabashia K.,
RA Thompson R.P.H., Powell J.J.;
RT "Immunolocalization of duodenal cytochrome B: a relationship with
RT circulating markers of iron status.";
RL Eur. J. Clin. Invest. 36:890-898(2006).
RN [20]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=17068337; DOI=10.1074/jbc.m606543200;
RA Su D., May J.M., Koury M.J., Asard H.;
RT "Human erythrocyte membranes contain a cytochrome b561 that may be involved
RT in extracellular ascorbate recycling.";
RL J. Biol. Chem. 281:39852-39859(2006).
RN [21]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=16510471; DOI=10.1152/ajplung.00342.2005;
RA Turi J.L., Wang X., McKie A.T., Nozik-Grayck E., Mamo L.B., Crissman K.,
RA Piantadosi C.A., Ghio A.J.;
RT "Duodenal cytochrome b: a novel ferrireductase in airway epithelial
RT cells.";
RL Am. J. Physiol. 291:L272-L280(2006).
RN [22] {ECO:0007744|PDB:5ZLE, ECO:0007744|PDB:5ZLG}
RP X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) IN COMPLEX WITH HEME B; ASCORBATE
RP AND ZINC, FUNCTION, CATALYTIC ACTIVITY, COFACTOR, ACTIVITY REGULATION,
RP SUBUNIT, TOPOLOGY, REGION, AND MUTAGENESIS OF PHE-58; LYS-79; LYS-83;
RP ASN-107; HIS-108; TYR-117; TYR-131; ARG-152 AND PHE-184.
RX PubMed=30272000; DOI=10.1038/s42003-018-0121-8;
RA Ganasen M., Togashi H., Takeda H., Asakura H., Tosha T., Yamashita K.,
RA Hirata K., Nariai Y., Urano T., Yuan X., Hamza I., Mauk A.G., Shiro Y.,
RA Sugimoto H., Sawai H.;
RT "Structural basis for promotion of duodenal iron absorption by enteric
RT ferric reductase with ascorbate.";
RL Commun. Biol. 1:120-120(2018).
CC -!- FUNCTION: Plasma membrane reductase that uses cytoplasmic ascorbate as
CC an electron donor to reduce extracellular Fe(3+) into Fe(2+)
CC (PubMed:30272000). Probably functions in dietary iron absorption at the
CC brush border of duodenal enterocytes by producing Fe(2+), the divalent
CC form of iron that can be transported into enterocytes
CC (PubMed:30272000). It is also able to reduce extracellular monodehydro-
CC L-ascorbate and may be involved in extracellular ascorbate regeneration
CC by erythrocytes in blood (PubMed:17068337). May also act as a
CC ferrireductase in airway epithelial cells (Probable). May also function
CC as a cupric transmembrane reductase (By similarity).
CC {ECO:0000250|UniProtKB:Q925G2, ECO:0000269|PubMed:17068337,
CC ECO:0000269|PubMed:30272000, ECO:0000305|PubMed:16510471}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Fe(3+)(out) + L-ascorbate(in) = Fe(2+)(out) + H(+) +
CC monodehydro-L-ascorbate radical(in); Xref=Rhea:RHEA:30403,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:29033, ChEBI:CHEBI:29034,
CC ChEBI:CHEBI:38290, ChEBI:CHEBI:59513; EC=7.2.1.3;
CC Evidence={ECO:0000269|PubMed:17068337, ECO:0000269|PubMed:30272000};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:30404;
CC Evidence={ECO:0000305|PubMed:17068337};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Cu(2+)(out) + L-ascorbate(in) = Cu(+)(out) + H(+) +
CC monodehydro-L-ascorbate radical(in); Xref=Rhea:RHEA:66656,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:29036, ChEBI:CHEBI:38290,
CC ChEBI:CHEBI:49552, ChEBI:CHEBI:59513;
CC Evidence={ECO:0000250|UniProtKB:Q925G2};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66657;
CC Evidence={ECO:0000250|UniProtKB:Q925G2};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-ascorbate(in) + monodehydro-L-ascorbate radical(out) = L-
CC ascorbate(out) + monodehydro-L-ascorbate radical(in);
CC Xref=Rhea:RHEA:66524, ChEBI:CHEBI:38290, ChEBI:CHEBI:59513;
CC Evidence={ECO:0000269|PubMed:17068337};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66525;
CC Evidence={ECO:0000305|PubMed:17068337};
CC -!- COFACTOR:
CC Name=heme b; Xref=ChEBI:CHEBI:60344;
CC Evidence={ECO:0000269|PubMed:30272000};
CC Note=Binds 2 heme b groups non-covalently.
CC {ECO:0000269|PubMed:30272000};
CC -!- ACTIVITY REGULATION: Activated by chelators like citrate, malate, and
CC oxalate specially at alkaline pH. {ECO:0000269|PubMed:30272000}.
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:30272000}.
CC -!- INTERACTION:
CC Q53TN4; P55212: CASP6; NbExp=3; IntAct=EBI-8637742, EBI-718729;
CC Q53TN4; Q14318: FKBP8; NbExp=3; IntAct=EBI-8637742, EBI-724839;
CC Q53TN4; Q96F15: GIMAP5; NbExp=3; IntAct=EBI-8637742, EBI-6166686;
CC Q53TN4; O14653: GOSR2; NbExp=3; IntAct=EBI-8637742, EBI-4401517;
CC Q53TN4; P09601: HMOX1; NbExp=3; IntAct=EBI-8637742, EBI-2806151;
CC Q53TN4; P13473-2: LAMP2; NbExp=3; IntAct=EBI-8637742, EBI-21591415;
CC Q53TN4; Q9UBY5: LPAR3; NbExp=3; IntAct=EBI-8637742, EBI-12033434;
CC Q53TN4; Q04941: PLP2; NbExp=3; IntAct=EBI-8637742, EBI-608347;
CC Q53TN4; O75400-2: PRPF40A; NbExp=3; IntAct=EBI-8637742, EBI-5280197;
CC Q53TN4; Q9UI14: RABAC1; NbExp=3; IntAct=EBI-8637742, EBI-712367;
CC Q53TN4; Q96IW7: SEC22A; NbExp=3; IntAct=EBI-8637742, EBI-8652744;
CC Q53TN4; Q9Y6X1: SERP1; NbExp=3; IntAct=EBI-8637742, EBI-10329948;
CC Q53TN4; Q8N6R1: SERP2; NbExp=3; IntAct=EBI-8637742, EBI-749270;
CC Q53TN4; Q9Y371: SH3GLB1; NbExp=3; IntAct=EBI-8637742, EBI-2623095;
CC Q53TN4; Q12846: STX4; NbExp=7; IntAct=EBI-8637742, EBI-744942;
CC Q53TN4; O15400: STX7; NbExp=3; IntAct=EBI-8637742, EBI-3221827;
CC Q53TN4; Q9BXJ8: TMEM120A; NbExp=3; IntAct=EBI-8637742, EBI-727322;
CC Q53TN4; Q6PI78: TMEM65; NbExp=3; IntAct=EBI-8637742, EBI-6656213;
CC Q53TN4; Q9P0L0: VAPA; NbExp=3; IntAct=EBI-8637742, EBI-1059156;
CC Q53TN4; O95292: VAPB; NbExp=3; IntAct=EBI-8637742, EBI-1188298;
CC Q53TN4; O95159: ZFPL1; NbExp=3; IntAct=EBI-8637742, EBI-718439;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:17068337};
CC Multi-pass membrane protein {ECO:0000269|PubMed:30272000}. Apical cell
CC membrane {ECO:0000305|PubMed:12949720}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:30272000}. Note=Localized at the brush border of
CC duodenal cells. {ECO:0000269|PubMed:12949720}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q53TN4-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q53TN4-2; Sequence=VSP_042039;
CC Name=3;
CC IsoId=Q53TN4-3; Sequence=VSP_044945;
CC -!- TISSUE SPECIFICITY: Present in erythrocyte membranes (at protein
CC level). Also expressed in respiratory epithelium.
CC {ECO:0000269|PubMed:16510471, ECO:0000269|PubMed:17068337}.
CC -!- INDUCTION: By iron deficiency (at protein level).
CC {ECO:0000269|PubMed:12949720, ECO:0000269|PubMed:17087784}.
CC -!- POLYMORPHISM: Genetic variations in CYBRD1 may act as modifier of iron
CC overload expression and account for the variance observed in serum
CC ferritin levels in patients with hereditary hemochromatosis.
CC {ECO:0000305|PubMed:16521311, ECO:0000305|PubMed:16521312,
CC ECO:0000305|PubMed:19673882}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAG29366.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
CC Sequence=CAG29367.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR EMBL; AL136693; CAB66628.1; -; mRNA.
DR EMBL; AK027115; BAB15661.1; -; mRNA.
DR EMBL; AK128495; BAC87466.1; -; mRNA.
DR EMBL; AK291731; BAF84420.1; -; mRNA.
DR EMBL; AK301485; BAG62999.1; -; mRNA.
DR EMBL; AK316588; BAG38176.1; -; mRNA.
DR EMBL; DQ496101; ABF47090.1; -; Genomic_DNA.
DR EMBL; AC007969; AAY14730.1; -; Genomic_DNA.
DR EMBL; CH471058; EAX11210.1; -; Genomic_DNA.
DR EMBL; BC065290; AAH65290.1; -; mRNA.
DR EMBL; AJ715523; CAG29366.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AJ715524; CAG29367.1; ALT_SEQ; Genomic_DNA.
DR CCDS; CCDS2244.1; -. [Q53TN4-1]
DR CCDS; CCDS46449.1; -. [Q53TN4-2]
DR CCDS; CCDS58736.1; -. [Q53TN4-3]
DR RefSeq; NP_001120855.1; NM_001127383.1. [Q53TN4-2]
DR RefSeq; NP_001243838.1; NM_001256909.1. [Q53TN4-3]
DR RefSeq; NP_079119.3; NM_024843.3. [Q53TN4-1]
DR PDB; 5ZLE; X-ray; 2.60 A; A=1-286.
DR PDB; 5ZLG; X-ray; 2.80 A; A=1-286.
DR PDBsum; 5ZLE; -.
DR PDBsum; 5ZLG; -.
DR AlphaFoldDB; Q53TN4; -.
DR SMR; Q53TN4; -.
DR BioGRID; 122984; 66.
DR IntAct; Q53TN4; 60.
DR MINT; Q53TN4; -.
DR STRING; 9606.ENSP00000319141; -.
DR DrugBank; DB13257; Ferrous sulfate anhydrous.
DR DrugBank; DB14520; Tetraferric tricitrate decahydrate.
DR TCDB; 5.B.2.1.3; the eukaryotic cytochrome b561 (cytb561) family.
DR iPTMnet; Q53TN4; -.
DR PhosphoSitePlus; Q53TN4; -.
DR SwissPalm; Q53TN4; -.
DR BioMuta; CYBRD1; -.
DR DMDM; 74726934; -.
DR EPD; Q53TN4; -.
DR jPOST; Q53TN4; -.
DR MassIVE; Q53TN4; -.
DR MaxQB; Q53TN4; -.
DR PaxDb; Q53TN4; -.
DR PeptideAtlas; Q53TN4; -.
DR PRIDE; Q53TN4; -.
DR ProteomicsDB; 5331; -.
DR ProteomicsDB; 62547; -. [Q53TN4-1]
DR Antibodypedia; 19375; 109 antibodies from 29 providers.
DR DNASU; 79901; -.
DR Ensembl; ENST00000321348.9; ENSP00000319141.4; ENSG00000071967.12. [Q53TN4-1]
DR Ensembl; ENST00000375252.3; ENSP00000364401.3; ENSG00000071967.12. [Q53TN4-2]
DR Ensembl; ENST00000409484.5; ENSP00000386739.1; ENSG00000071967.12. [Q53TN4-3]
DR GeneID; 79901; -.
DR KEGG; hsa:79901; -.
DR MANE-Select; ENST00000321348.9; ENSP00000319141.4; NM_024843.4; NP_079119.3.
DR UCSC; uc002ugy.5; human. [Q53TN4-1]
DR CTD; 79901; -.
DR DisGeNET; 79901; -.
DR GeneCards; CYBRD1; -.
DR HGNC; HGNC:20797; CYBRD1.
DR HPA; ENSG00000071967; Low tissue specificity.
DR MIM; 605745; gene.
DR neXtProt; NX_Q53TN4; -.
DR OpenTargets; ENSG00000071967; -.
DR PharmGKB; PA134970061; -.
DR VEuPathDB; HostDB:ENSG00000071967; -.
DR eggNOG; KOG1619; Eukaryota.
DR GeneTree; ENSGT00950000183197; -.
DR HOGENOM; CLU_069712_1_2_1; -.
DR InParanoid; Q53TN4; -.
DR OMA; SAEFNWH; -.
DR OrthoDB; 1503869at2759; -.
DR PhylomeDB; Q53TN4; -.
DR TreeFam; TF314222; -.
DR BioCyc; MetaCyc:HS01046-MON; -.
DR BRENDA; 7.2.1.3; 2681.
DR PathwayCommons; Q53TN4; -.
DR Reactome; R-HSA-917937; Iron uptake and transport.
DR SignaLink; Q53TN4; -.
DR BioGRID-ORCS; 79901; 24 hits in 1076 CRISPR screens.
DR ChiTaRS; CYBRD1; human.
DR GenomeRNAi; 79901; -.
DR Pharos; Q53TN4; Tbio.
DR PRO; PR:Q53TN4; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; Q53TN4; protein.
DR Bgee; ENSG00000071967; Expressed in calcaneal tendon and 177 other tissues.
DR ExpressionAtlas; Q53TN4; baseline and differential.
DR Genevisible; Q53TN4; HS.
DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB.
DR GO; GO:0031526; C:brush border membrane; IDA:UniProtKB.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IDA:UniProtKB.
DR GO; GO:0005765; C:lysosomal membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0016491; F:oxidoreductase activity; IBA:GO_Central.
DR GO; GO:0016722; F:oxidoreductase activity, acting on metal ions; IDA:HGNC-UCL.
DR GO; GO:0140571; F:transmembrane ascorbate ferrireductase activity; IDA:UniProtKB.
DR GO; GO:0140575; F:transmembrane monodehydroascorbate reductase activity; IDA:UniProtKB.
DR GO; GO:0140576; P:ascorbate homeostasis; IDA:UniProtKB.
DR GO; GO:0006879; P:cellular iron ion homeostasis; IDA:ARUK-UCL.
DR GO; GO:0055072; P:iron ion homeostasis; IDA:UniProtKB.
DR GO; GO:0033215; P:reductive iron assimilation; IC:UniProtKB.
DR GO; GO:0010039; P:response to iron ion; IEA:Ensembl.
DR DisProt; DP03005; -.
DR InterPro; IPR043205; CYB561/CYBRD1-like.
DR InterPro; IPR028838; CYBRD1.
DR InterPro; IPR006593; Cyt_b561/ferric_Rdtase_TM.
DR PANTHER; PTHR10106; PTHR10106; 1.
DR PANTHER; PTHR10106:SF12; PTHR10106:SF12; 1.
DR Pfam; PF03188; Cytochrom_B561; 1.
DR SMART; SM00665; B561; 1.
DR PROSITE; PS50939; CYTOCHROME_B561; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Electron transport;
KW Heme; Iron; Membrane; Metal-binding; Oxidoreductase; Phosphoprotein;
KW Reference proteome; Translocase; Transmembrane; Transmembrane helix;
KW Transport.
FT CHAIN 1..286
FT /note="Plasma membrane ascorbate-dependent reductase
FT CYBRD1"
FT /id="PRO_0000314830"
FT TOPO_DOM 1..7
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:30272000"
FT TRANSMEM 8..32
FT /note="Helical; Name=1"
FT /evidence="ECO:0000269|PubMed:30272000,
FT ECO:0007744|PDB:5ZLE, ECO:0007744|PDB:5ZLG"
FT TOPO_DOM 33..47
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:30272000"
FT TRANSMEM 48..69
FT /note="Helical; Name=2"
FT /evidence="ECO:0000269|PubMed:30272000,
FT ECO:0007744|PDB:5ZLE, ECO:0007744|PDB:5ZLG"
FT TOPO_DOM 70..78
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:30272000"
FT TRANSMEM 79..105
FT /note="Helical; Name=3"
FT /evidence="ECO:0000269|PubMed:30272000,
FT ECO:0007744|PDB:5ZLE, ECO:0007744|PDB:5ZLG"
FT TOPO_DOM 106..118
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:30272000"
FT TRANSMEM 119..144
FT /note="Helical; Name=4"
FT /evidence="ECO:0000269|PubMed:30272000,
FT ECO:0007744|PDB:5ZLE, ECO:0007744|PDB:5ZLG"
FT TOPO_DOM 145..151
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:30272000"
FT TRANSMEM 152..179
FT /note="Helical; Name=5"
FT /evidence="ECO:0000269|PubMed:30272000,
FT ECO:0007744|PDB:5ZLE, ECO:0007744|PDB:5ZLG"
FT TOPO_DOM 180..197
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:30272000"
FT TRANSMEM 198..222
FT /note="Helical; Name=6"
FT /evidence="ECO:0000269|PubMed:30272000,
FT ECO:0007744|PDB:5ZLE, ECO:0007744|PDB:5ZLG"
FT TOPO_DOM 223..286
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:30272000"
FT DOMAIN 15..220
FT /note="Cytochrome b561"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00242"
FT REGION 229..268
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 248..263
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 50
FT /ligand="heme b"
FT /ligand_id="ChEBI:CHEBI:60344"
FT /ligand_label="1"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000269|PubMed:30272000,
FT ECO:0007744|PDB:5ZLE, ECO:0007744|PDB:5ZLG"
FT BINDING 70
FT /ligand="heme b"
FT /ligand_id="ChEBI:CHEBI:60344"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:30272000,
FT ECO:0007744|PDB:5ZLE, ECO:0007744|PDB:5ZLG"
FT BINDING 79
FT /ligand="heme b"
FT /ligand_id="ChEBI:CHEBI:60344"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:30272000,
FT ECO:0007744|PDB:5ZLE, ECO:0007744|PDB:5ZLG"
FT BINDING 79
FT /ligand="L-ascorbate"
FT /ligand_id="ChEBI:CHEBI:38290"
FT /evidence="ECO:0000269|PubMed:30272000,
FT ECO:0007744|PDB:5ZLE, ECO:0007744|PDB:5ZLG"
FT BINDING 83
FT /ligand="L-ascorbate"
FT /ligand_id="ChEBI:CHEBI:38290"
FT /evidence="ECO:0000269|PubMed:30272000,
FT ECO:0007744|PDB:5ZLE, ECO:0007744|PDB:5ZLG"
FT BINDING 86
FT /ligand="heme b"
FT /ligand_id="ChEBI:CHEBI:60344"
FT /ligand_label="2"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000269|PubMed:30272000,
FT ECO:0007744|PDB:5ZLE, ECO:0007744|PDB:5ZLG"
FT BINDING 108
FT /ligand="Fe(3+)"
FT /ligand_id="ChEBI:CHEBI:29034"
FT /ligand_note="substrate"
FT /evidence="ECO:0000269|PubMed:30272000,
FT ECO:0007744|PDB:5ZLE, ECO:0007744|PDB:5ZLG"
FT BINDING 115..118
FT /ligand="heme b"
FT /ligand_id="ChEBI:CHEBI:60344"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:30272000,
FT ECO:0007744|PDB:5ZLE, ECO:0007744|PDB:5ZLG"
FT BINDING 120
FT /ligand="heme b"
FT /ligand_id="ChEBI:CHEBI:60344"
FT /ligand_label="1"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000269|PubMed:30272000,
FT ECO:0007744|PDB:5ZLE, ECO:0007744|PDB:5ZLG"
FT BINDING 152
FT /ligand="L-ascorbate"
FT /ligand_id="ChEBI:CHEBI:38290"
FT /evidence="ECO:0000269|PubMed:30272000,
FT ECO:0007744|PDB:5ZLE, ECO:0007744|PDB:5ZLG"
FT BINDING 159
FT /ligand="heme b"
FT /ligand_id="ChEBI:CHEBI:60344"
FT /ligand_label="2"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000269|PubMed:30272000,
FT ECO:0007744|PDB:5ZLE, ECO:0007744|PDB:5ZLG"
FT BINDING 180
FT /ligand="heme b"
FT /ligand_id="ChEBI:CHEBI:60344"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:30272000,
FT ECO:0007744|PDB:5ZLE, ECO:0007744|PDB:5ZLG"
FT BINDING 225
FT /ligand="heme b"
FT /ligand_id="ChEBI:CHEBI:60344"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:30272000,
FT ECO:0007744|PDB:5ZLE, ECO:0007744|PDB:5ZLG"
FT MOD_RES 232
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 285
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:23186163"
FT VAR_SEQ 1..64
FT /note="MAMEGYWRFLALLGSALLVGFLSVIFALVWVLHYREGLGWDGSALEFNWHPV
FT LMVTGFVFIQGI -> MLDEGE (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_044945"
FT VAR_SEQ 66..286
FT /note="IIVYRLPWTWKCSKLLMKSIHAGLNAVAAILAIISVVAVFENHNVNNIANMY
FT SLHSWVGLIAVICYLLQLLSGFSVFLLPWAPLSLRAFLMPIHVYSGIVIFGTVIATALM
FT GLTEKLIFSLRDPAYSTFPPEGVFVNTLGLLILVFGALIFWIVTRPQWKRPKEPNSTIL
FT HPNGGTEQGARGSMPAYSGNNMDKSDSELNSEVAARKRNLALDEAGQRSTM -> SFRF
FT FSLSASMGSAFSPSISHAHTCLFWNCHLWNSDCNSTYGIDRETDFFPERSCIQYIPARR
FT CFRKYAWPSDPGVRGPHFLDSHQTAMETS (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_042039"
FT VARIANT 156
FT /note="M -> T (in dbSNP:rs16859487)"
FT /evidence="ECO:0000269|PubMed:14702039"
FT /id="VAR_038065"
FT VARIANT 226
FT /note="R -> H (in some patients with hereditary
FT hemochromatosis; dbSNP:rs62181680)"
FT /evidence="ECO:0000269|PubMed:15338274,
FT ECO:0000269|PubMed:16521301"
FT /id="VAR_038066"
FT VARIANT 266
FT /note="S -> N (in dbSNP:rs10455)"
FT /evidence="ECO:0000269|PubMed:11230166,
FT ECO:0000269|PubMed:15489334, ECO:0000269|Ref.3,
FT ECO:0000269|Ref.5"
FT /id="VAR_038067"
FT MUTAGEN 58
FT /note="F->L: Decreased transmembrane ascorbate
FT ferrireductase activity."
FT /evidence="ECO:0000269|PubMed:30272000"
FT MUTAGEN 79
FT /note="K->S: Decreased heme b reduction by ascorbate."
FT /evidence="ECO:0000269|PubMed:30272000"
FT MUTAGEN 83
FT /note="K->S: Decreased heme b reduction by ascorbate."
FT /evidence="ECO:0000269|PubMed:30272000"
FT MUTAGEN 107
FT /note="N->A,F: Decreased transmembrane ascorbate
FT ferrireductase activity."
FT /evidence="ECO:0000269|PubMed:30272000"
FT MUTAGEN 108
FT /note="H->A: Loss of transmembrane ascorbate ferrireductase
FT activity."
FT /evidence="ECO:0000269|PubMed:30272000"
FT MUTAGEN 108
FT /note="H->Q: Loss of iron binding. Loss of transmembrane
FT ascorbate ferrireductase activity."
FT /evidence="ECO:0000269|PubMed:30272000"
FT MUTAGEN 117
FT /note="Y->A,S: Decreased transmembrane ascorbate
FT ferrireductase activity."
FT /evidence="ECO:0000269|PubMed:30272000"
FT MUTAGEN 131
FT /note="Y->L: Decreased transmembrane ascorbate
FT ferrireductase activity."
FT /evidence="ECO:0000269|PubMed:30272000"
FT MUTAGEN 152
FT /note="R->E: Decreased heme b reduction by ascorbate."
FT /evidence="ECO:0000269|PubMed:30272000"
FT MUTAGEN 184
FT /note="F->A: Decreased transmembrane ascorbate
FT ferrireductase activity."
FT /evidence="ECO:0000269|PubMed:30272000"
FT CONFLICT 7
FT /note="W -> R (in Ref. 1; CAB66628)"
FT /evidence="ECO:0000305"
FT HELIX 7..33
FT /evidence="ECO:0007829|PDB:5ZLE"
FT STRAND 40..43
FT /evidence="ECO:0007829|PDB:5ZLE"
FT HELIX 44..47
FT /evidence="ECO:0007829|PDB:5ZLE"
FT HELIX 49..57
FT /evidence="ECO:0007829|PDB:5ZLE"
FT HELIX 60..66
FT /evidence="ECO:0007829|PDB:5ZLE"
FT HELIX 67..70
FT /evidence="ECO:0007829|PDB:5ZLE"
FT HELIX 72..74
FT /evidence="ECO:0007829|PDB:5ZLE"
FT HELIX 79..111
FT /evidence="ECO:0007829|PDB:5ZLE"
FT HELIX 119..142
FT /evidence="ECO:0007829|PDB:5ZLE"
FT HELIX 149..185
FT /evidence="ECO:0007829|PDB:5ZLE"
FT TURN 187..190
FT /evidence="ECO:0007829|PDB:5ZLE"
FT HELIX 191..193
FT /evidence="ECO:0007829|PDB:5ZLE"
FT HELIX 196..219
FT /evidence="ECO:0007829|PDB:5ZLE"
FT HELIX 222..224
FT /evidence="ECO:0007829|PDB:5ZLE"
SQ SEQUENCE 286 AA; 31641 MW; 09AA921925A077F7 CRC64;
MAMEGYWRFL ALLGSALLVG FLSVIFALVW VLHYREGLGW DGSALEFNWH PVLMVTGFVF
IQGIAIIVYR LPWTWKCSKL LMKSIHAGLN AVAAILAIIS VVAVFENHNV NNIANMYSLH
SWVGLIAVIC YLLQLLSGFS VFLLPWAPLS LRAFLMPIHV YSGIVIFGTV IATALMGLTE
KLIFSLRDPA YSTFPPEGVF VNTLGLLILV FGALIFWIVT RPQWKRPKEP NSTILHPNGG
TEQGARGSMP AYSGNNMDKS DSELNSEVAA RKRNLALDEA GQRSTM
