FOLR2_HUMAN
ID FOLR2_HUMAN Reviewed; 255 AA.
AC P14207; Q05CA5; Q6GTE8;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 4.
DT 03-AUG-2022, entry version 184.
DE RecName: Full=Folate receptor beta;
DE Short=FR-beta;
DE AltName: Full=Folate receptor 2;
DE AltName: Full=Folate receptor, fetal/placental;
DE AltName: Full=Placental folate-binding protein;
DE Short=FBP;
DE Flags: Precursor;
GN Name=FOLR2;
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 [GENOMIC DNA], AND TISSUE SPECIFICITY.
RX PubMed=8445646; DOI=10.1006/jmbi.1993.1116;
RA Page S.T., Owen W.C., Price K., Elwood P.C.;
RT "Expression of the human placental folate receptor transcript is regulated
RT in human tissues. Organization and full nucleotide sequence of the gene.";
RL J. Mol. Biol. 229:1175-1183(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE, FUNCTION, TISSUE
RP SPECIFICITY, GLYCOSYLATION, AND SUBCELLULAR LOCATION.
RC TISSUE=Placenta;
RX PubMed=2605182; DOI=10.1021/bi00446a042;
RA Ratnam M., Marquardt H., Duhring J.L., Freisheim J.H.;
RT "Homologous membrane folate binding proteins in human placenta: cloning and
RT sequence of a cDNA.";
RL Biochemistry 28:8249-8254(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Placenta;
RX PubMed=8106441; DOI=10.1016/s0021-9258(17)37605-6;
RA Sadasivan E., Cedeno M.M., Rothenberg S.P.;
RT "Characterization of the gene encoding a folate-binding protein expressed
RT in human placenta. Identification of promoter activity in a G-rich SP1 site
RT linked with the tandemly repeated GGAAG motif for the ets encoded GA-
RT binding protein.";
RL J. Biol. Chem. 269:4725-4735(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Cerebellum;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pancreas, and Placenta;
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 [6]
RP PROTEIN SEQUENCE OF 68-86; 102-120 AND 173-184.
RX PubMed=2561247; DOI=10.1016/0065-2571(89)90091-5;
RA Freisheim J.H., Price E.M., Ratnam M.;
RT "Folate coenzyme and antifolate transport proteins in normal and neoplastic
RT cells.";
RL Adv. Enzyme Regul. 29:13-26(1989).
RN [7]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=4066659; DOI=10.1016/s0021-9258(18)95679-6;
RA Antony A.C., Kane M.A., Portillo R.M., Elwood P.C., Kolhouse J.F.;
RT "Studies of the role of a particulate folate-binding protein in the uptake
RT of 5-methyltetrahydrofolate by cultured human KB cells.";
RL J. Biol. Chem. 260:14911-14917(1985).
RN [8]
RP GPI-ANCHOR AT ASN-230.
RX PubMed=7578066; DOI=10.1021/bi00044a039;
RA Yan W., Ratnam M.;
RT "Preferred sites of glycosylphosphatidylinositol modification in folate
RT receptors and constraints in the primary structure of the hydrophobic
RT portion of the signal.";
RL Biochemistry 34:14594-14600(1995).
RN [9]
RP PROTEOLYTIC PROCESSING.
RX PubMed=9398177; DOI=10.1021/bi970845w;
RA Wang J., Shen F., Yan W., Wu M., Ratnam M.;
RT "Proteolysis of the carboxyl-terminal GPI signal independent of GPI
RT modification as a mechanism for selective protein secretion.";
RL Biochemistry 36:14583-14592(1997).
RN [10]
RP INDUCTION BY RETINOIC ACID.
RX PubMed=20632143; DOI=10.1007/s13277-010-0074-0;
RA Xu Y., Wang T., Tang R., Tang S.;
RT "All-trans retinoic acid is capable of inducing folate receptor beta
RT expression in KG-1 cells.";
RL Tumor Biol. 31:589-595(2010).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 24-228 IN COMPLEXES WITH FOLATE
RP AND THE ANTIFOLATES METHOTREXATE; AMINOPTERIN AND PEMETREXED, FUNCTION,
RP GLYCOSYLATION AT ASN-115 AND ASN-195, AND DISULFIDE BONDS.
RX PubMed=23934049; DOI=10.1073/pnas.1308827110;
RA Wibowo A.S., Singh M., Reeder K.M., Carter J.J., Kovach A.R., Meng W.,
RA Ratnam M., Zhang F., Dann C.E. III;
RT "Structures of human folate receptors reveal biological trafficking states
RT and diversity in folate and antifolate recognition.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:15180-15188(2013).
RN [12]
RP VARIANT [LARGE SCALE ANALYSIS] ASN-236.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Binds to folate and reduced folic acid derivatives and
CC mediates delivery of 5-methyltetrahydrofolate and folate analogs into
CC the interior of cells. Has high affinity for folate and folic acid
CC analogs at neutral pH. Exposure to slightly acidic pH after receptor
CC endocytosis triggers a conformation change that strongly reduces its
CC affinity for folates and mediates their release.
CC {ECO:0000269|PubMed:23934049, ECO:0000269|PubMed:2605182,
CC ECO:0000269|PubMed:4066659}.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor, GPI-anchor. Secreted
CC {ECO:0000305}.
CC -!- TISSUE SPECIFICITY: Expressed in placenta and hematopoietic cells.
CC Expression is increased in malignant tissues.
CC {ECO:0000269|PubMed:2605182, ECO:0000269|PubMed:8445646}.
CC -!- INDUCTION: Up-regulated by retinoic acid.
CC {ECO:0000269|PubMed:20632143}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:23934049,
CC ECO:0000269|PubMed:2605182}.
CC -!- SIMILARITY: Belongs to the folate receptor family. {ECO:0000305}.
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DR EMBL; X69516; CAA49267.1; -; Genomic_DNA.
DR EMBL; J02876; AAA35821.1; -; mRNA.
DR EMBL; U02714; AAA17370.1; -; Genomic_DNA.
DR EMBL; U02716; AAA17370.1; JOINED; Genomic_DNA.
DR EMBL; AK222643; BAD96363.1; -; mRNA.
DR EMBL; BC058036; AAH58036.1; -; mRNA.
DR EMBL; BC027894; AAH27894.1; -; mRNA.
DR CCDS; CCDS8212.1; -.
DR PIR; A53315; A33417.
DR RefSeq; NP_000794.3; NM_000803.4.
DR RefSeq; NP_001107006.1; NM_001113534.1.
DR RefSeq; NP_001107007.1; NM_001113535.1.
DR RefSeq; NP_001107008.1; NM_001113536.1.
DR PDB; 4KMY; X-ray; 1.80 A; A=24-228.
DR PDB; 4KMZ; X-ray; 2.30 A; A=24-228.
DR PDB; 4KN0; X-ray; 2.10 A; A=24-228.
DR PDB; 4KN1; X-ray; 2.30 A; A=24-228.
DR PDB; 4KN2; X-ray; 2.60 A; A/B/C=24-227.
DR PDBsum; 4KMY; -.
DR PDBsum; 4KMZ; -.
DR PDBsum; 4KN0; -.
DR PDBsum; 4KN1; -.
DR PDBsum; 4KN2; -.
DR AlphaFoldDB; P14207; -.
DR SMR; P14207; -.
DR BioGRID; 108633; 2.
DR STRING; 9606.ENSP00000298223; -.
DR BindingDB; P14207; -.
DR ChEMBL; CHEMBL5064; -.
DR DrugBank; DB00158; Folic acid.
DR DrugBank; DB00563; Methotrexate.
DR DrugBank; DB05168; Vintafolide.
DR DrugCentral; P14207; -.
DR GlyGen; P14207; 3 sites.
DR iPTMnet; P14207; -.
DR PhosphoSitePlus; P14207; -.
DR BioMuta; FOLR2; -.
DR DMDM; 116241366; -.
DR jPOST; P14207; -.
DR MassIVE; P14207; -.
DR PaxDb; P14207; -.
DR PeptideAtlas; P14207; -.
DR PRIDE; P14207; -.
DR ProteomicsDB; 53031; -.
DR ABCD; P14207; 4 sequenced antibodies.
DR Antibodypedia; 30818; 351 antibodies from 32 providers.
DR DNASU; 2350; -.
DR Ensembl; ENST00000298223.11; ENSP00000298223.6; ENSG00000165457.15.
DR GeneID; 2350; -.
DR KEGG; hsa:2350; -.
DR MANE-Select; ENST00000298223.11; ENSP00000298223.6; NM_000803.5; NP_000794.3.
DR UCSC; uc001ose.5; human.
DR CTD; 2350; -.
DR DisGeNET; 2350; -.
DR GeneCards; FOLR2; -.
DR HGNC; HGNC:3793; FOLR2.
DR HPA; ENSG00000165457; Tissue enhanced (placenta).
DR MIM; 136425; gene.
DR neXtProt; NX_P14207; -.
DR OpenTargets; ENSG00000165457; -.
DR PharmGKB; PA28209; -.
DR VEuPathDB; HostDB:ENSG00000165457; -.
DR eggNOG; KOG3656; Eukaryota.
DR GeneTree; ENSGT00950000183144; -.
DR InParanoid; P14207; -.
DR OMA; CRKWTDV; -.
DR OrthoDB; 1534387at2759; -.
DR PhylomeDB; P14207; -.
DR TreeFam; TF328532; -.
DR PathwayCommons; P14207; -.
DR Reactome; R-HSA-163125; Post-translational modification: synthesis of GPI-anchored proteins.
DR Reactome; R-HSA-196757; Metabolism of folate and pterines.
DR BioGRID-ORCS; 2350; 12 hits in 1073 CRISPR screens.
DR ChiTaRS; FOLR2; human.
DR GeneWiki; FOLR2; -.
DR GenomeRNAi; 2350; -.
DR Pharos; P14207; Tchem.
DR PRO; PR:P14207; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; P14207; protein.
DR Bgee; ENSG00000165457; Expressed in gall bladder and 180 other tissues.
DR ExpressionAtlas; P14207; baseline and differential.
DR Genevisible; P14207; HS.
DR GO; GO:0031362; C:anchored component of external side of plasma membrane; IDA:UniProtKB.
DR GO; GO:0009986; C:cell surface; IDA:BHF-UCL.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0005542; F:folic acid binding; IDA:UniProtKB.
DR GO; GO:0061714; F:folic acid receptor activity; IDA:UniProtKB.
DR GO; GO:0038023; F:signaling receptor activity; IBA:GO_Central.
DR GO; GO:0007155; P:cell adhesion; IBA:GO_Central.
DR GO; GO:1904447; P:folate import across plasma membrane; IEA:InterPro.
DR GO; GO:0015884; P:folic acid transport; IDA:UniProtKB.
DR GO; GO:0007342; P:fusion of sperm to egg plasma membrane involved in single fertilization; IBA:GO_Central.
DR GO; GO:0006954; P:inflammatory response; NAS:BHF-UCL.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IMP:BHF-UCL.
DR GO; GO:0035036; P:sperm-egg recognition; IBA:GO_Central.
DR InterPro; IPR004269; Folate_rcpt.
DR InterPro; IPR018143; Folate_rcpt-like.
DR InterPro; IPR032937; FOLR2.
DR PANTHER; PTHR10517; PTHR10517; 1.
DR PANTHER; PTHR10517:SF8; PTHR10517:SF8; 1.
DR Pfam; PF03024; Folate_rec; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Direct protein sequencing; Disulfide bond;
KW Folate-binding; Glycoprotein; GPI-anchor; Lipoprotein; Membrane; Receptor;
KW Reference proteome; Secreted; Signal; Transport.
FT SIGNAL 1..16
FT CHAIN 17..230
FT /note="Folate receptor beta"
FT /id="PRO_0000008806"
FT PROPEP 231..255
FT /note="Removed in mature form"
FT /id="PRO_0000008807"
FT BINDING 97
FT /ligand="folate"
FT /ligand_id="ChEBI:CHEBI:62501"
FT /evidence="ECO:0007744|PDB:4KMZ"
FT BINDING 101
FT /ligand="folate"
FT /ligand_id="ChEBI:CHEBI:62501"
FT /evidence="ECO:0007744|PDB:4KMZ"
FT BINDING 118..122
FT /ligand="folate"
FT /ligand_id="ChEBI:CHEBI:62501"
FT /evidence="ECO:0007744|PDB:4KMZ"
FT BINDING 151..156
FT /ligand="folate"
FT /ligand_id="ChEBI:CHEBI:62501"
FT /evidence="ECO:0007744|PDB:4KMZ"
FT BINDING 190
FT /ligand="folate"
FT /ligand_id="ChEBI:CHEBI:62501"
FT /evidence="ECO:0007744|PDB:4KMZ"
FT LIPID 230
FT /note="GPI-anchor amidated asparagine"
FT /evidence="ECO:0000269|PubMed:7578066"
FT CARBOHYD 115
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:23934049,
FT ECO:0007744|PDB:4KN0"
FT CARBOHYD 195
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:23934049,
FT ECO:0007744|PDB:4KMZ, ECO:0007744|PDB:4KN0,
FT ECO:0007744|PDB:4KN1, ECO:0007744|PDB:4KN2"
FT DISULFID 31..59
FT /evidence="ECO:0000269|PubMed:23934049,
FT ECO:0007744|PDB:4KMY, ECO:0007744|PDB:4KMZ,
FT ECO:0007744|PDB:4KN0, ECO:0007744|PDB:4KN1,
FT ECO:0007744|PDB:4KN2"
FT DISULFID 51..99
FT /evidence="ECO:0000269|PubMed:23934049,
FT ECO:0007744|PDB:4KMY, ECO:0007744|PDB:4KMZ,
FT ECO:0007744|PDB:4KN0, ECO:0007744|PDB:4KN1,
FT ECO:0007744|PDB:4KN2"
FT DISULFID 60..103
FT /evidence="ECO:0000269|PubMed:23934049,
FT ECO:0007744|PDB:4KMY, ECO:0007744|PDB:4KMZ,
FT ECO:0007744|PDB:4KN0, ECO:0007744|PDB:4KN1,
FT ECO:0007744|PDB:4KN2"
FT DISULFID 83..169
FT /evidence="ECO:0000269|PubMed:23934049,
FT ECO:0007744|PDB:4KMY, ECO:0007744|PDB:4KMZ,
FT ECO:0007744|PDB:4KN0, ECO:0007744|PDB:4KN1,
FT ECO:0007744|PDB:4KN2"
FT DISULFID 90..140
FT /evidence="ECO:0000269|PubMed:23934049,
FT ECO:0007744|PDB:4KMY, ECO:0007744|PDB:4KMZ,
FT ECO:0007744|PDB:4KN0, ECO:0007744|PDB:4KN1,
FT ECO:0007744|PDB:4KN2"
FT DISULFID 129..203
FT /evidence="ECO:0000269|PubMed:23934049,
FT ECO:0007744|PDB:4KMY, ECO:0007744|PDB:4KMZ,
FT ECO:0007744|PDB:4KN0, ECO:0007744|PDB:4KN1,
FT ECO:0007744|PDB:4KN2"
FT DISULFID 133..183
FT /evidence="ECO:0000269|PubMed:23934049,
FT ECO:0007744|PDB:4KMY, ECO:0007744|PDB:4KMZ,
FT ECO:0007744|PDB:4KN0, ECO:0007744|PDB:4KN1,
FT ECO:0007744|PDB:4KN2"
FT DISULFID 146..163
FT /evidence="ECO:0000269|PubMed:23934049,
FT ECO:0007744|PDB:4KMY, ECO:0007744|PDB:4KMZ,
FT ECO:0007744|PDB:4KN0, ECO:0007744|PDB:4KN1,
FT ECO:0007744|PDB:4KN2"
FT VARIANT 236
FT /note="H -> N (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036408"
FT CONFLICT 103
FT /note="C -> V (in Ref. 6; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 111..112
FT /note="IQ -> VR (in Ref. 6; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 115
FT /note="N -> D (in Ref. 6; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 117
FT /note="S -> T (in Ref. 2; AAA35821, 3; AAA17370 and 6; AA
FT sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 141
FT /note="H -> L (in Ref. 3; AAA17370)"
FT /evidence="ECO:0000305"
FT CONFLICT 244
FT /note="S -> R (in Ref. 3; AAA17370)"
FT /evidence="ECO:0000305"
FT HELIX 24..27
FT /evidence="ECO:0007829|PDB:4KMY"
FT STRAND 33..36
FT /evidence="ECO:0007829|PDB:4KMZ"
FT HELIX 49..54
FT /evidence="ECO:0007829|PDB:4KMY"
FT STRAND 57..60
FT /evidence="ECO:0007829|PDB:4KMY"
FT HELIX 62..68
FT /evidence="ECO:0007829|PDB:4KMY"
FT STRAND 74..76
FT /evidence="ECO:0007829|PDB:4KMY"
FT TURN 80..83
FT /evidence="ECO:0007829|PDB:4KMY"
FT HELIX 88..103
FT /evidence="ECO:0007829|PDB:4KMY"
FT HELIX 108..110
FT /evidence="ECO:0007829|PDB:4KMY"
FT STRAND 111..116
FT /evidence="ECO:0007829|PDB:4KMY"
FT STRAND 119..123
FT /evidence="ECO:0007829|PDB:4KMY"
FT STRAND 126..128
FT /evidence="ECO:0007829|PDB:4KN0"
FT HELIX 130..140
FT /evidence="ECO:0007829|PDB:4KMY"
FT STRAND 144..146
FT /evidence="ECO:0007829|PDB:4KMY"
FT STRAND 150..152
FT /evidence="ECO:0007829|PDB:4KN0"
FT HELIX 172..175
FT /evidence="ECO:0007829|PDB:4KMY"
FT HELIX 179..185
FT /evidence="ECO:0007829|PDB:4KMY"
FT TURN 186..188
FT /evidence="ECO:0007829|PDB:4KMY"
FT STRAND 189..191
FT /evidence="ECO:0007829|PDB:4KMY"
FT STRAND 200..204
FT /evidence="ECO:0007829|PDB:4KMY"
FT HELIX 216..223
FT /evidence="ECO:0007829|PDB:4KMY"
SQ SEQUENCE 255 AA; 29280 MW; F585715CF5631C98 CRC64;
MVWKWMPLLL LLVCVATMCS AQDRTDLLNV CMDAKHHKTK PGPEDKLHDQ CSPWKKNACC
TASTSQELHK DTSRLYNFNW DHCGKMEPAC KRHFIQDTCL YECSPNLGPW IQQVNQSWRK
ERFLDVPLCK EDCQRWWEDC HTSHTCKSNW HRGWDWTSGV NKCPAGALCR TFESYFPTPA
ALCEGLWSHS YKVSNYSRGS GRCIQMWFDS AQGNPNEEVA RFYAAAMHVN AGEMLHGTGG
LLLSLALMLQ LWLLG
