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Protein

Transferrin receptor protein 1

Gene

TFRC

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Cellular uptake of iron occurs via receptor-mediated endocytosis of ligand-occupied transferrin receptor into specialized endosomes. Endosomal acidification leads to iron release. The apotransferrin-receptor complex is then recycled to the cell surface with a return to neutral pH and the concomitant loss of affinity of apotransferrin for its receptor. Transferrin receptor is necessary for development of erythrocytes and the nervous system (By similarity). A second ligand, the heditary hemochromatosis protein HFE, competes for binding with transferrin for an overlapping C-terminal binding site. Positively regulates T and B cell proliferation through iron uptake (PubMed:26642240).By similarity2 Publications
(Microbial infection) Acts as a receptor for new-world arenaviruses: Guanarito, Junin and Machupo virus.2 Publications

Miscellaneous

Serum transferrin receptor (sTfR) is used as a means of detecting erythropoietin (EPO) misuse by athletes and as a diagnostic test for anemia resulting from a number of conditions including rheumatoid arthritis, pregnancy, irritable bowel syndrome and in HIV patients.
Canine and feline parvoviruses bind human and feline transferrin receptors and use these receptors to enter and infect cells.

GO - Molecular functioni

  • double-stranded RNA binding Source: MGI
  • identical protein binding Source: IntAct
  • protein homodimerization activity Source: BHF-UCL
  • RNA binding Source: UniProtKB
  • transferrin receptor activity Source: UniProtKB
  • transferrin transmembrane transporter activity Source: InterPro
  • virus receptor activity Source: UniProtKB-KW

GO - Biological processi

  • cellular iron ion homeostasis Source: ProtInc
  • cellular response to drug Source: MGI
  • cellular response to leukemia inhibitory factor Source: Ensembl
  • iron ion import Source: UniProtKB
  • membrane organization Source: Reactome
  • osteoclast differentiation Source: Ensembl
  • positive regulation of B cell proliferation Source: UniProtKB
  • positive regulation of bone resorption Source: Ensembl
  • positive regulation of isotype switching Source: UniProtKB
  • positive regulation of T cell proliferation Source: UniProtKB
  • receptor internalization Source: UniProtKB
  • transferrin transport Source: UniProtKB

Keywordsi

Molecular functionHost cell receptor for virus entry, Receptor
Biological processEndocytosis, Host-virus interaction

Enzyme and pathway databases

ReactomeiR-HSA-432722 Golgi Associated Vesicle Biogenesis
R-HSA-8856825 Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828 Clathrin-mediated endocytosis
R-HSA-917977 Transferrin endocytosis and recycling
SIGNORiP02786

Protein family/group databases

MEROPSiM28.972
TCDBi9.B.229.1.1 the transferrin receptor, cd71, (tfr) family

Names & Taxonomyi

Protein namesi
Recommended name:
Transferrin receptor protein 1
Short name:
TR
Short name:
TfR
Short name:
TfR1
Short name:
Trfr
Alternative name(s):
T9
p90
CD_antigen: CD71
Cleaved into the following chain:
Gene namesi
Name:TFRC
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 3

Organism-specific databases

EuPathDBiHostDB:ENSG00000072274.12
HGNCiHGNC:11763 TFRC
MIMi190010 gene
neXtProtiNX_P02786

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 67CytoplasmicSequence analysisAdd BLAST67
Transmembranei68 – 88Helical; Signal-anchor for type II membrane proteinSequence analysisAdd BLAST21
Topological domaini89 – 760ExtracellularSequence analysisAdd BLAST672

Keywords - Cellular componenti

Cell membrane, Membrane, Secreted

Pathology & Biotechi

Involvement in diseasei

Immunodeficiency 46 (IMD46)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn autosomal recessive primary immunodeficiency disorder characterized by early-onset chronic diarrhea, recurrent infections, hypo- or agammaglobulinemia, normal lymphocyte counts, intermittent neutropenia, and intermittent thrombocytopenia.
See also OMIM:616740
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07636520Y → H in IMD46; increases protein expression; increases cell surface expression on T and B cells; increases soluble form level; impairs receptor internalization; impairs transferrin transport; impairs T and B cell proliferation as well as B cell class-switching; interacts with STEAP3; doesn't affect receptor internalization in erythroid precursor cells. 1 PublicationCorresponds to variant dbSNP:rs863225436EnsemblClinVar.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi9 – 12FSNL → YTRF: Only 80% as active as wild-type receptor. 4
Mutagenesisi20 – 34YTRFS…DGDNS → PPGYSLARQVDYTRF: No influence on endocytic uptake of the receptor. Add BLAST15
Mutagenesisi20 – 23YTRF → PPGY: Only 16% as active as wild-type receptor. 1 Publication4
Mutagenesisi20Y → C: Only 35% as active as wild-type receptor. 3 Publications1
Mutagenesisi20Y → G: Only 20% as active as wild-type receptor. 3 Publications1
Mutagenesisi21T → F: Only 88% as active as wild-type receptor. 1 Publication1
Mutagenesisi21T → TA: Only 14% as active as wild-type receptor. 1 Publication1
Mutagenesisi21T → TAA: Only 19% as active as wild-type receptor. 1 Publication1
Mutagenesisi23F → Y: Only 48% as active as wild-type receptor. 1 Publication1
Mutagenesisi31 – 34GDNS → YTRF: 2-fold increase of the endocytic uptake of the receptor. 4
Mutagenesisi47 – 50NADN → YTRF: 1.27-fold increase of the endocytic uptake of the receptor. 4
Mutagenesisi619L → A: 20-fold reduced affinity for transferrin receptor. No binding to HFE. 1
Mutagenesisi622V → A: No significant effect on binding to transferrin nor HFE. 1
Mutagenesisi623R → A: No significant effect on binding to transferrin nor HFE. 1
Mutagenesisi629R → A: >5-fold reduced affinity for transferrin. >10-fold reduced affinity for HFE. 1
Mutagenesisi640Q → A: No effect on binding to transferrin. >10-fold reduced affinity for HFE. 1
Mutagenesisi641W → A: No significant effect on binding to transferrin nor HFE. 1
Mutagenesisi643Y → A: 20-fold reduced affinity for transferrin. No binding to HFE. 1
Mutagenesisi644S → A: No significant effect on binding to transferrin nor HFE. 1
Mutagenesisi646R → A or H: No binding to transferrin. 1 Publication1
Mutagenesisi646R → K: 5% binding to transferrin. 1 Publication1
Mutagenesisi647G → A: Large effect on affinity for transferrin. 4-fold reduced affinity for HFE. 1 Publication1
Mutagenesisi648D → A: 16% binding to transferrin. 1 Publication1
Mutagenesisi648D → E: 57% binding to transferrin. 1 Publication1
Mutagenesisi650F → Q: >5-fold reduced affinity for transferrin. >10-fold reduced affinity for HFE. 1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi7037
MalaCardsiTFRC
MIMi616740 phenotype
OpenTargetsiENSG00000072274
PharmGKBiPA36478

Chemistry databases

DrugBankiDB09412 Gallium citrate Ga-67
DB05260 Gallium nitrate

Polymorphism and mutation databases

BioMutaiTFRC
DMDMi108935939

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001741321 – 760Transferrin receptor protein 1Add BLAST760
ChainiPRO_0000292265101 – 760Transferrin receptor protein 1, serum formAdd BLAST660

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei10PhosphoserineCombined sources1
Modified residuei19PhosphoserineBy similarity1
Modified residuei20PhosphotyrosineCombined sources1
Modified residuei21PhosphothreonineCombined sources1
Modified residuei24Phosphoserine1 Publication1
Lipidationi62S-palmitoyl cysteine1 Publication1
Lipidationi67S-palmitoyl cysteine1 Publication1
Disulfide bondi89Interchain
Disulfide bondi98Interchain
GlycosylationiCAR_000072104O-linked (GalNAc...) threonine2 Publications1
Glycosylationi251N-linked (GlcNAc...) asparagineCombined sources4 Publications1
Glycosylationi317N-linked (GlcNAc...) asparagineCombined sources1 Publication1
GlycosylationiCAR_000173727N-linked (GlcNAc...) asparagineCombined sources3 Publications1

Post-translational modificationi

N- and O-glycosylated, phosphorylated and palmitoylated. The serum form is only glycosylated.6 Publications
Proteolytically cleaved on Arg-100 to produce the soluble serum form (sTfR).
Palmitoylated on both Cys-62 and Cys-67. Cys-62 seems to be the major site of palmitoylation.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei100 – 101Cleavage; by trypsin; to produce soluble form2

Keywords - PTMi

Disulfide bond, Glycoprotein, Lipoprotein, Palmitate, Phosphoprotein

Proteomic databases

EPDiP02786
MaxQBiP02786
PaxDbiP02786
PeptideAtlasiP02786
PRIDEiP02786

PTM databases

GlyConnecti607
iPTMnetiP02786
PhosphoSitePlusiP02786
SwissPalmiP02786
UniCarbKBiP02786

Expressioni

Inductioni

Regulated by cellular iron levels through binding of the iron regulatory proteins, IRP1 and IRP2, to iron-responsive elements in the 3'-UTR. Up-regulated upon mitogenic stimulation.

Gene expression databases

BgeeiENSG00000072274
CleanExiHS_TFRC
ExpressionAtlasiP02786 baseline and differential
GenevisibleiP02786 HS

Organism-specific databases

HPAiCAB000153
HPA028598

Interactioni

Subunit structurei

Homodimer; disulfide-linked. Binds one transferrin or HFE molecule per subunit. Binds the HLA class II histocompatibility antigen, DR1. Interacts with SH3BP3. Interacts with STEAP3; facilitates TFRC endocytosis in erythroid precursor cells (PubMed:26642240).2 Publications
(Microbial infection) Interacts with Guanarito, Junin and Machupo arenavirus glycoprotein complex (PubMed:17287727, PubMed:18268337).2 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • identical protein binding Source: IntAct
  • protein homodimerization activity Source: BHF-UCL

Protein-protein interaction databases

BioGridi112895, 90 interactors
CORUMiP02786
DIPiDIP-2736N
ELMiP02786
IntActiP02786, 76 interactors
MINTiP02786
STRINGi9606.ENSP00000353224

Structurei

Secondary structure

1760
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi124 – 136Combined sources13
Helixi140 – 146Combined sources7
Turni150 – 152Combined sources3
Helixi160 – 176Combined sources17
Beta strandi179 – 192Combined sources14
Beta strandi199 – 204Combined sources6
Turni205 – 208Combined sources4
Beta strandi209 – 214Combined sources6
Beta strandi220 – 222Combined sources3
Beta strandi226 – 230Combined sources5
Beta strandi232 – 234Combined sources3
Turni236 – 238Combined sources3
Helixi240 – 244Combined sources5
Beta strandi245 – 248Combined sources4
Beta strandi253 – 259Combined sources7
Helixi264 – 272Combined sources9
Turni273 – 275Combined sources3
Beta strandi277 – 282Combined sources6
Turni285 – 287Combined sources3
Beta strandi303 – 306Combined sources4
Beta strandi308 – 310Combined sources3
Beta strandi311 – 313Combined sources3
Helixi317 – 319Combined sources3
Beta strandi334 – 336Combined sources3
Helixi339 – 346Combined sources8
Beta strandi349 – 352Combined sources4
Helixi355 – 357Combined sources3
Beta strandi364 – 367Combined sources4
Beta strandi371 – 377Combined sources7
Beta strandi380 – 393Combined sources14
Beta strandi396 – 408Combined sources13
Beta strandi411 – 413Combined sources3
Turni416 – 419Combined sources4
Helixi420 – 438Combined sources19
Beta strandi445 – 455Combined sources11
Helixi456 – 458Combined sources3
Helixi461 – 469Combined sources9
Turni470 – 473Combined sources4
Helixi474 – 476Combined sources3
Beta strandi478 – 483Combined sources6
Beta strandi491 – 498Combined sources8
Helixi500 – 502Combined sources3
Helixi503 – 510Combined sources8
Turni516 – 518Combined sources3
Beta strandi520 – 522Combined sources3
Helixi528 – 531Combined sources4
Helixi541 – 546Combined sources6
Beta strandi552 – 558Combined sources7
Turni564 – 567Combined sources4
Helixi573 – 579Combined sources7
Helixi583 – 603Combined sources21
Beta strandi604 – 606Combined sources3
Helixi613 – 625Combined sources13
Helixi626 – 628Combined sources3
Turni629 – 636Combined sources8
Helixi640 – 662Combined sources23
Helixi668 – 680Combined sources13
Helixi682 – 685Combined sources4
Beta strandi688 – 690Combined sources3
Turni692 – 694Combined sources3
Turni700 – 702Combined sources3
Beta strandi705 – 708Combined sources4
Helixi709 – 717Combined sources9
Turni718 – 722Combined sources5
Helixi728 – 749Combined sources22
Helixi753 – 755Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1CX8X-ray3.20A/B/C/D/E/F/G/H122-760[»]
1DE4X-ray2.80C/F/I121-760[»]
1SUVelectron microscopy7.50A/B122-760[»]
2NSUelectron microscopy27.00A/B122-760[»]
3KASX-ray2.40A121-760[»]
3S9LX-ray3.22A/B120-760[»]
3S9MX-ray3.32A/B120-760[»]
3S9NX-ray3.25A/B120-760[»]
ProteinModelPortaliP02786
SMRiP02786
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP02786

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini223 – 313PAAdd BLAST91

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 67Mediates interaction with SH3BP41 PublicationAdd BLAST67
Regioni569 – 760Ligand-bindingAdd BLAST192

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi20 – 23Endocytosis signal4
Motifi58 – 61Stop-transfer sequence4
Motifi646 – 648Cell attachment site; required for binding to transferrin3

Sequence similaritiesi

Belongs to the peptidase M28 family. M28B subfamily.Curated

Keywords - Domaini

Signal-anchor, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG2195 Eukaryota
COG2234 LUCA
GeneTreeiENSGT00550000074421
HOVERGENiHBG023177
InParanoidiP02786
KOiK06503
OMAiDNSHVEM
OrthoDBiEOG091G02ZM
PhylomeDBiP02786
TreeFamiTF312981

Family and domain databases

CDDicd02128 PA_TfR, 1 hit
Gene3Di1.20.930.40, 1 hit
InterProiView protein in InterPro
IPR003137 PA_domain
IPR007484 Peptidase_M28
IPR029513 TfR
IPR007365 TFR-like_dimer_dom
IPR036757 TFR-like_dimer_dom_sf
IPR037324 TfR1/2_PA
PANTHERiPTHR10404:SF26 PTHR10404:SF26, 1 hit
PfamiView protein in Pfam
PF02225 PA, 1 hit
PF04389 Peptidase_M28, 1 hit
PF04253 TFR_dimer, 1 hit
SUPFAMiSSF47672 SSF47672, 1 hit

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P02786-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MMDQARSAFS NLFGGEPLSY TRFSLARQVD GDNSHVEMKL AVDEEENADN
60 70 80 90 100
NTKANVTKPK RCSGSICYGT IAVIVFFLIG FMIGYLGYCK GVEPKTECER
110 120 130 140 150
LAGTESPVRE EPGEDFPAAR RLYWDDLKRK LSEKLDSTDF TGTIKLLNEN
160 170 180 190 200
SYVPREAGSQ KDENLALYVE NQFREFKLSK VWRDQHFVKI QVKDSAQNSV
210 220 230 240 250
IIVDKNGRLV YLVENPGGYV AYSKAATVTG KLVHANFGTK KDFEDLYTPV
260 270 280 290 300
NGSIVIVRAG KITFAEKVAN AESLNAIGVL IYMDQTKFPI VNAELSFFGH
310 320 330 340 350
AHLGTGDPYT PGFPSFNHTQ FPPSRSSGLP NIPVQTISRA AAEKLFGNME
360 370 380 390 400
GDCPSDWKTD STCRMVTSES KNVKLTVSNV LKEIKILNIF GVIKGFVEPD
410 420 430 440 450
HYVVVGAQRD AWGPGAAKSG VGTALLLKLA QMFSDMVLKD GFQPSRSIIF
460 470 480 490 500
ASWSAGDFGS VGATEWLEGY LSSLHLKAFT YINLDKAVLG TSNFKVSASP
510 520 530 540 550
LLYTLIEKTM QNVKHPVTGQ FLYQDSNWAS KVEKLTLDNA AFPFLAYSGI
560 570 580 590 600
PAVSFCFCED TDYPYLGTTM DTYKELIERI PELNKVARAA AEVAGQFVIK
610 620 630 640 650
LTHDVELNLD YERYNSQLLS FVRDLNQYRA DIKEMGLSLQ WLYSARGDFF
660 670 680 690 700
RATSRLTTDF GNAEKTDRFV MKKLNDRVMR VEYHFLSPYV SPKESPFRHV
710 720 730 740 750
FWGSGSHTLP ALLENLKLRK QNNGAFNETL FRNQLALATW TIQGAANALS
760
GDVWDIDNEF
Length:760
Mass (Da):84,871
Last modified:May 30, 2006 - v2
Checksum:iC886F14000D90154
GO

Sequence cautioni

The sequence BAD92491 differs from that shown. Reason: Erroneous initiation.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti104T → K AA sequence (PubMed:1871153).Curated1
Sequence conflicti109R → V AA sequence (PubMed:1871153).Curated1
Sequence conflicti123Y → T AA sequence (PubMed:1871153).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07636520Y → H in IMD46; increases protein expression; increases cell surface expression on T and B cells; increases soluble form level; impairs receptor internalization; impairs transferrin transport; impairs T and B cell proliferation as well as B cell class-switching; interacts with STEAP3; doesn't affect receptor internalization in erythroid precursor cells. 1 PublicationCorresponds to variant dbSNP:rs863225436EnsemblClinVar.1
Natural variantiVAR_012737142G → S Rare polymorphism. 3 PublicationsCorresponds to variant dbSNP:rs3817672Ensembl.1
Natural variantiVAR_051806212L → V. Corresponds to variant dbSNP:rs41301381Ensembl.1
Natural variantiVAR_051807420G → S. Corresponds to variant dbSNP:rs41295879Ensembl.1
Natural variantiVAR_051808677R → H. Corresponds to variant dbSNP:rs41298067Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X01060 mRNA Translation: CAA25527.1
M11507 mRNA Translation: AAA61153.1
AF187320 Genomic DNA Translation: AAF04564.1
AB209254 mRNA Translation: BAD92491.1 Different initiation.
DQ496099 Genomic DNA Translation: ABF47088.1
CH471191 Genomic DNA Translation: EAW53670.1
CH471191 Genomic DNA Translation: EAW53673.1
BC001188 mRNA Translation: AAH01188.1
CCDSiCCDS3312.1
PIRiA93343 JXHU
RefSeqiNP_001121620.1, NM_001128148.2
NP_001300894.1, NM_001313965.1
NP_001300895.1, NM_001313966.1
NP_003225.2, NM_003234.3
UniGeneiHs.529618

Genome annotation databases

EnsembliENST00000360110; ENSP00000353224; ENSG00000072274
ENST00000392396; ENSP00000376197; ENSG00000072274
GeneIDi7037
KEGGihsa:7037
UCSCiuc003fvz.5 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiTFR1_HUMAN
AccessioniPrimary (citable) accession number: P02786
Secondary accession number(s): D3DXB0
, Q1HE24, Q59G55, Q9UCN0, Q9UCU5, Q9UDF9, Q9UK21
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 21, 1986
Last sequence update: May 30, 2006
Last modified: May 23, 2018
This is version 223 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

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