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P15328 (FOLR1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 136. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Folate receptor alpha

Short name=FR-alpha
Alternative name(s):
Adult folate-binding protein
Short name=FBP
Folate receptor 1
Folate receptor, adult
KB cells FBP
Ovarian tumor-associated antigen MOv18
Gene names
Name:FOLR1
Synonyms:FOLR
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length257 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells. Has high affinity for folate and folic acid analogs at neutral pH. Exposure to slightly acidic pH after receptor endocytosis triggers a conformation change that strongly reduces its affinity for folates and mediates their release. Required for normal embryonic development and normal cell proliferation. Ref.2 Ref.14 Ref.16 Ref.22 Ref.23

Subcellular location

Cell membrane; Lipid-anchorGPI-anchor. Secreted Probable. Cytoplasmic vesicle. Cytoplasmic vesicleclathrin-coated vesicle. Endosome. Apical cell membrane By similarity. Note: Endocytosed into cytoplasmic vesicles and then recycled to the cell membrane. Ref.1 Ref.2 Ref.13 Ref.14 Ref.15 Ref.16 Ref.19

Tissue specificity

Primarily expressed in tissues of epithelial origin. Expression is increased in malignant tissues. Expressed in kidney, lung and cerebellum. Detected in placenta and thymus epithelium. Ref.1 Ref.2 Ref.6

Post-translational modification

The secreted form is derived from the membrane-bound form either by cleavage of the GPI anchor, or/and by proteolysis catalyzed by a metalloprotease.

Involvement in disease

Neurodegeneration due to cerebral folate transport deficiency (NCFTD) [MIM:613068]: A neurodegenerative disorder resulting from brain-specific folate deficiency early in life. Onset is apparent in late infancy with severe developmental regression, movement disturbances, epilepsy and leukodystrophy.
Note: The disease is caused by mutations affecting the gene represented in this entry.

Sequence similarities

Belongs to the folate receptor family.

Ontologies

Keywords
   Biological processTransport
   Cellular componentCell membrane
Cytoplasmic vesicle
Endosome
Membrane
Secreted
   Coding sequence diversityPolymorphism
   DiseaseNeurodegeneration
   DomainSignal
   LigandFolate-binding
   Molecular functionReceptor
   PTMDisulfide bond
Glycoprotein
GPI-anchor
Lipoprotein
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processcell death

Inferred from electronic annotation. Source: UniProtKB-KW

folic acid metabolic process

Inferred from electronic annotation. Source: Ensembl

folic acid transport

Inferred from mutant phenotype Ref.14. Source: UniProtKB

receptor-mediated endocytosis

Traceable author statement PubMed 9545095. Source: ProtInc

   Cellular_componentanchored component of external side of plasma membrane

Inferred from direct assay Ref.2Ref.14. Source: UniProtKB

apical plasma membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

brush border membrane

Inferred from electronic annotation. Source: Ensembl

clathrin-coated vesicle

Inferred from electronic annotation. Source: UniProtKB-SubCell

endosome

Inferred from electronic annotation. Source: UniProtKB-SubCell

extracellular vesicular exosome

Inferred from direct assay PubMed 19199708. Source: UniProt

integral component of plasma membrane

Traceable author statement PubMed 10633085. Source: ProtInc

membrane

Traceable author statement Ref.1. Source: ProtInc

plasma membrane

Non-traceable author statement Ref.4. Source: UniProtKB

   Molecular_functionfolic acid binding

Inferred from direct assay Ref.22Ref.2. Source: UniProtKB

folic acid transporter activity

Inferred from mutant phenotype Ref.14. Source: UniProtKB

receptor activity

Traceable author statement PubMed 10633085. Source: ProtInc

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2424 Potential
Chain25 – 234210Folate receptor alpha
PRO_0000008802
Propeptide235 – 25723Removed in mature form
PRO_0000008803

Regions

Region124 – 1285Folate binding
Region157 – 1626Folate binding

Sites

Binding site1031Folate
Binding site1071Folate
Binding site1961Folate

Amino acid modifications

Lipidation2341GPI-anchor amidated serine Ref.15 Ref.17 Ref.18 Ref.19
Glycosylation691N-linked (GlcNAc...) Ref.22 Ref.23
Glycosylation1611N-linked (GlcNAc...) Ref.20 Ref.22 Ref.23
Glycosylation2011N-linked (GlcNAc...) Ref.20 Ref.22 Ref.23
Disulfide bond37 ↔ 65 Ref.22 Ref.23
Disulfide bond57 ↔ 105 Ref.22 Ref.23
Disulfide bond66 ↔ 109 Ref.22 Ref.23
Disulfide bond89 ↔ 175 Ref.22 Ref.23
Disulfide bond96 ↔ 146 Ref.22 Ref.23
Disulfide bond135 ↔ 209 Ref.22 Ref.23
Disulfide bond139 ↔ 189 Ref.22 Ref.23
Disulfide bond152 ↔ 169 Ref.22 Ref.23

Natural variations

Natural variant281W → R.
Corresponds to variant rs7928649 [ dbSNP | Ensembl ].
VAR_059284
Natural variant1601W → C.
Corresponds to variant rs1801932 [ dbSNP | Ensembl ].
VAR_011963

Experimental info

Mutagenesis821Y → A: Slightly reduced affinity for folate. Ref.22
Mutagenesis1031D → A: Strongly reduced affinity for folate. Ref.22
Mutagenesis1071Y → A: Moderately reduced affinity for folate. Ref.22
Mutagenesis1241W → A: Moderately reduced affinity for folate. Ref.22
Mutagenesis1251R → A: Moderately reduced affinity for folate. Ref.22
Mutagenesis1281R → A: Moderately reduced affinity for folate. Ref.22
Mutagenesis1571H → A: Moderately reduced affinity for folate. Ref.22
Mutagenesis1621W → A: Moderately reduced affinity for folate. Ref.22
Mutagenesis1961S → A: Moderately reduced affinity for folate. Ref.22
Sequence conflict1801F → L in BAD97247. Ref.9
Sequence conflict1841T → S in AAA74896. Ref.12

Secondary structure

........................................... 257
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P15328 [UniParc].

Last modified June 1, 1994. Version 3.
Checksum: D458D8BB047C96A6

FASTA25729,819
        10         20         30         40         50         60 
MAQRMTTQLL LLLVWVAVVG EAQTRIAWAR TELLNVCMNA KHHKEKPGPE DKLHEQCRPW 

        70         80         90        100        110        120 
RKNACCSTNT SQEAHKDVSY LYRFNWNHCG EMAPACKRHF IQDTCLYECS PNLGPWIQQV 

       130        140        150        160        170        180 
DQSWRKERVL NVPLCKEDCE QWWEDCRTSY TCKSNWHKGW NWTSGFNKCA VGAACQPFHF 

       190        200        210        220        230        240 
YFPTPTVLCN EIWTHSYKVS NYSRGSGRCI QMWFDPAQGN PNEEVARFYA AAMSGAGPWA 

       250 
AWPFLLSLAL MLLWLLS 

« Hide

References

« Hide 'large scale' references
[1]"Molecular cloning and characterization of the human folate-binding protein cDNA from placenta and malignant tissue culture (KB) cells."
Elwood P.C.
J. Biol. Chem. 264:14893-14901(1989) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE, SUBCELLULAR LOCATION, GLYCOSYLATION, TISSUE SPECIFICITY.
[2]"Complementary DNA for the folate binding protein correctly predicts anchoring to the membrane by glycosyl-phosphatidylinositol."
Lacey S.W., Sanders J.M., Rothberg K.G., Anderson R.G.W., Kamen B.A.
J. Clin. Invest. 84:715-720(1989) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[3]"Folate-binding protein is a marker for ovarian cancer."
Campbell I.G., Jones T.A., Foulkes W.D., Trowsdale J.
Cancer Res. 51:5329-5338(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Ovary.
[4]"Cloning of a tumor-associated antigen: MOv18 and MOv19 antibodies recognize a folate-binding protein."
Coney L.R., Tomassetti A., Carayannopoulos L., Frasca V., Kamen B.A., Colnaghi M.I., Zurawski V.R. Jr.
Cancer Res. 51:6125-6132(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 31-56.
Tissue: Ovarian carcinoma.
[5]"Genomic organization of the gene and a related pseudogene for a human folate binding protein."
Sadasivan E., Cedeno M., Rothenberg S.P.
Biochim. Biophys. Acta 1131:91-94(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[6]"The divergent 5' termini of the alpha human folate receptor (hFR) mRNAs originate from two tissue-specific promoters and alternative splicing: characterization of the alpha hFR gene structure."
Elwood P.C., Nachmanoff K., Saikawa Y., Page S.T., Pacheco P., Roberts S., Chung K.-N.
Biochemistry 36:1467-1478(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], NUCLEOTIDE SEQUENCE [MRNA] OF 1-56, TISSUE SPECIFICITY.
Tissue: Lymphocyte.
[7]"Cloning of human full-length CDSs in BD Creator(TM) system donor vector."
Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A.
Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[8]"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)."
Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S., Neubert P., Kstrang K., Schatten R., Shen B., Henze S., Mar W., Korn B., Zuo D., Hu Y., LaBaer J.
Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[9]Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.
Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Kidney proximal tubule.
[10]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[11]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Placenta.
[12]"The complete amino acid sequence of a human folate binding protein from KB cells determined from the cDNA."
Sadasivan E., Rothenberg S.P.
J. Biol. Chem. 264:5806-5811(1989) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 24-249.
[13]"Purified membrane and soluble folate binding proteins from cultured KB cells have similar amino acid compositions and molecular weights but differ in fatty acid acylation."
Luhrs C.A., Pitiranggon P., da Costa M., Rothenberg S.P., Slomiany B.L., Brink L., Tous G.I., Stein S.
Proc. Natl. Acad. Sci. U.S.A. 84:6546-6549(1987) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 26-43, SUBCELLULAR LOCATION.
[14]"UMSCC38 cells amplified at 11q13 for the folate receptor synthesize a mutant nonfunctional folate receptor."
Orr R.B., Kamen B.A.
Cancer Res. 54:3905-3911(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION.
[15]"Preferred sites of glycosylphosphatidylinositol modification in folate receptors and constraints in the primary structure of the hydrophobic portion of the signal."
Yan W., Ratnam M.
Biochemistry 34:14594-14600(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: GPI-ANCHOR AT SER-234, SUBCELLULAR LOCATION.
[16]"Endocytosis of GPI-linked membrane folate receptor-alpha."
Rijnboutt S., Jansen G., Posthuma G., Hynes J.B., Schornagel J.H., Strous G.J.
J. Cell Biol. 132:35-47(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, GLYCOSYLATION, SUBCELLULAR LOCATION.
[17]"Proteomic analysis of glycosylphosphatidylinositol-anchored membrane proteins."
Elortza F., Nuehse T.S., Foster L.J., Stensballe A., Peck S.C., Jensen O.N.
Mol. Cell. Proteomics 2:1261-1270(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: GPI-ANCHOR [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[18]"Modification-specific proteomics of plasma membrane proteins: identification and characterization of glycosylphosphatidylinositol-anchored proteins released upon phospholipase D treatment."
Elortza F., Mohammed S., Bunkenborg J., Foster L.J., Nuehse T.S., Brodbeck U., Peck S.C., Jensen O.N.
J. Proteome Res. 5:935-943(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: GPI-ANCHOR [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[19]"Computational approach for identification and characterization of GPI-anchored peptides in proteomics experiments."
Omaetxebarria M.J., Elortza F., Rodriguez-Suarez E., Aloria K., Arizmendi J.M., Jensen O.N., Matthiesen R.
Proteomics 7:1951-1960(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: GPI-ANCHOR AT SER-234, IDENTIFICATION BY MASS SPECTROMETRY.
[20]"Identification of N-linked glycoproteins in human milk by hydrophilic interaction liquid chromatography and mass spectrometry."
Picariello G., Ferranti P., Mamone G., Roepstorff P., Addeo F.
Proteomics 8:3833-3847(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-161 AND ASN-201.
Tissue: Milk.
[21]"Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism."
Steinfeld R., Grapp M., Kraetzner R., Dreha-Kulaczewski S., Helms G., Dechent P., Wevers R., Grosso S., Gaertner J.
Am. J. Hum. Genet. 85:354-363(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN NEURODEGENERATION DUE TO CEREBRAL FOLATE TRANSPORT DEFICIENCY.
[22]"Structural basis for molecular recognition of folic acid by folate receptors."
Chen C., Ke J., Zhou X.E., Yi W., Brunzelle J.S., Li J., Yong E.L., Xu H.E., Melcher K.
Nature 500:486-489(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 23-235 IN COMPLEX WITH FOLATE, FUNCTION, MUTAGENESIS OF TYR-82; ASP-103; TYR-107; TRP-124; ARG-125; ARG-128; HIS-157; TRP-162 AND SER-196, DISULFIDE BONDS, GLYCOSYLATION AT ASN-69; ASN-161 AND ASN-201.
[23]"Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition."
Wibowo A.S., Singh M., Reeder K.M., Carter J.J., Kovach A.R., Meng W., Ratnam M., Zhang F., Dann C.E. III
Proc. Natl. Acad. Sci. U.S.A. 110:15180-15188(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.55 ANGSTROMS) OF 30-234, FUNCTION, GLYCOSYLATION AT ASN-69; ASN-161 AND ASN-201, DISULFIDE BONDS.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
J05013 mRNA. Translation: AAA35823.1.
M28099 mRNA. Translation: AAA35822.1.
X62753 mRNA. Translation: CAA44610.1.
U20391 Genomic DNA. Translation: AAB05827.1.
U78793 mRNA. Translation: AAB39751.1.
U78794 mRNA. Translation: AAB39752.1.
BT007158 mRNA. Translation: AAP35822.1.
CR542019 mRNA. Translation: CAG46816.1.
AK223527 mRNA. Translation: BAD97247.1.
CH471076 Genomic DNA. Translation: EAW74848.1.
BC002947 mRNA. Translation: AAH02947.1.
M25317 mRNA. Translation: AAA74896.1.
PIRA45753. A44904.
RefSeqNP_000793.1. NM_000802.3.
NP_057936.1. NM_016724.2.
NP_057937.1. NM_016725.2.
NP_057941.1. NM_016729.2.
UniGeneHs.73769.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
4KM6X-ray1.55A30-234[»]
4KM7X-ray1.80A/B28-234[»]
4KMXX-ray2.20A28-234[»]
4LRHX-ray2.80A/B/C/D/E/F/G/H23-235[»]
ProteinModelPortalP15328.
SMRP15328. Positions 30-233.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid108631. 14 interactions.
IntActP15328. 11 interactions.
STRING9606.ENSP00000308137.

Chemistry

BindingDBP15328.
ChEMBLCHEMBL2121.

Protein family/group databases

TCDB9.B.92.1.1. the folate receptor (fr) family.

Polymorphism databases

DMDM544337.

Proteomic databases

PaxDbP15328.
PeptideAtlasP15328.
PRIDEP15328.

Protocols and materials databases

DNASU2348.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000312293; ENSP00000308137; ENSG00000110195.
ENST00000393676; ENSP00000377281; ENSG00000110195.
ENST00000393679; ENSP00000377284; ENSG00000110195.
ENST00000393681; ENSP00000377286; ENSG00000110195.
GeneID2348.
KEGGhsa:2348.
UCSCuc001orz.2. human.

Organism-specific databases

CTD2348.
GeneCardsGC11P071900.
HGNCHGNC:3791. FOLR1.
MIM136430. gene.
613068. phenotype.
neXtProtNX_P15328.
Orphanet217382. Neurodegenerative syndrome due to cerebral folate transport deficiency.
PharmGKBPA28207.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG26606.
HOGENOMHOG000006539.
HOVERGENHBG039612.
InParanoidP15328.
KOK13649.
OMANWTSGFN.
OrthoDBEOG7K6PW3.
PhylomeDBP15328.
TreeFamTF328532.

Gene expression databases

ArrayExpressP15328.
BgeeP15328.
CleanExHS_FOLR1.
GenevestigatorP15328.

Family and domain databases

InterProIPR004269. Folate_rcpt.
IPR018143. Folate_rcpt-like.
[Graphical view]
PANTHERPTHR10517. PTHR10517. 1 hit.
PfamPF03024. Folate_rec. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiFolate_receptor_1.
GenomeRNAi2348.
NextBio9519.
PROP15328.
SOURCESearch...

Entry information

Entry nameFOLR1_HUMAN
AccessionPrimary (citable) accession number: P15328
Secondary accession number(s): Q53EW2 expand/collapse secondary AC list , Q6FGT8, Q6LC90, Q9UCT2
Entry history
Integrated into UniProtKB/Swiss-Prot: April 1, 1990
Last sequence update: June 1, 1994
Last modified: April 16, 2014
This is version 136 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 11

Human chromosome 11: entries, gene names and cross-references to MIM