Transferrin receptor protein 1 (TFRC)
The protein contains 760 amino acids for an estimated molecular weight of 84871 Da.
Cellular uptake of iron occurs via receptor-mediated endocytosis of ligand-occupied transferrin receptor into specialized endosomes (PubMed:26214738). 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). Acts as a lipid sensor that regulates mitochondrial fusion by regulating activation of the JNK pathway (PubMed:26214738). When dietary levels of stearate (C18:0) are low, promotes activation of the JNK pathway, resulting in HUWE1-mediated ubiquitination and subsequent degradation of the mitofusin MFN2 and inhibition of mitochondrial fusion (PubMed:26214738). When dietary levels of stearate (C18:0) are high, TFRC stearoylation inhibits activation of the JNK pathway and thus degradation of the mitofusin MFN2 (PubMed:26214738).', '(Microbial infection) Acts as a receptor for new-world arenaviruses: Guanarito, Junin and Machupo virus. (updated: Aug. 12, 2020)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt, is predicted to be membranous by TOPCONS.
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| Variant | Description |
|---|---|
| dbSNP:rs3817672 | |
| dbSNP:rs41301381 | |
| dbSNP:rs41295879 | |
| dbSNP:rs41298067 | |
| IMD46 |
Biological Process
Cellular iron ion homeostasis
Cellular response to drug
Cellular response to leukemia inhibitory factor
Intracellular signal transduction
Iron ion import
Iron ion transport
Membrane organization
Negative regulation of apoptotic process
Negative regulation of mitochondrial fusion
Osteoclast differentiation
Positive regulation of B cell proliferation
Positive regulation of bone resorption
Positive regulation of gene expression
Positive regulation of I-kappaB kinase/NF-kappaB signaling
Positive regulation of isotype switching
Positive regulation of NF-kappaB transcription factor activity
Positive regulation of peptidyl-serine phosphorylation
Positive regulation of protein localization to nucleus
Positive regulation of protein phosphorylation
Positive regulation of protein-containing complex assembly
Positive regulation of T cell proliferation
Receptor internalization
Transferrin transport
Transmembrane transport
Transport across blood-brain barrier
Viral process
Cellular Component
Basolateral plasma membrane
Blood microparticle
Cell surface
Clathrin-coated endocytic vesicle membrane
Clathrin-coated pit
Clathrin-coated vesicle membrane
Cytoplasmic vesicle
Cytoplasmic, membrane-bounded vesicle
Early endosome
Endosome
Endosome membrane
External side of plasma membrane
Extracellular exosome
Extracellular region
Extracellular space
Extracellular vesicle
HFE-transferrin receptor complex
Integral component of plasma membrane
Intracellular membrane-bounded organelle
Melanosome
Membrane
Obsolete cell
Perinuclear region of cytoplasm
Plasma membrane
Recycling endosome
Vesicle
Molecular Function
Double-stranded RNA binding
Identical protein binding
Metalloexopeptidase activity
Obsolete transferrin transmembrane transporter activity
Poly(A) RNA binding
Protein homodimerization activity
Protein kinase binding
Protein-containing complex binding
RNA binding
Transferrin receptor activity
Virus receptor activity
The reference OMIM entry for this protein is 190010
Transferrin receptor; tfrc
Transferrin receptor 1; tfr1
Tfr
Trfr
Cd71
CLONING
A monoclonal antibody, OKT-9, recognizes an antigen ubiquitously distributed on the cell surface of actively growing human cells. It is a glycoprotein composed of disulfide-linked polypeptide chains, each of 90,000 daltons molecular weight. Immunoprecipitation of the OKT-9 antigen in the presence of labeled transferrin results in specific precipitation of transferrin (Sutherland et al., 1981); thus, the OKT-9 antigen is presumably transferrin receptor. Nikinmaa and Schroder (1987) concluded that p90 and TFRC are the same protein: studies using monoclonal antibodies indicated that exhaustive precipitation of radioactively labeled lysates with one antibody removed all activity of lysates with the other. Peptide maps of antigens recognized with both antibodies showed great similarity and indicated that both antibodies react with the same antigen, the human transferrin receptor, but with different antigenic sites of the molecule.GENE FUNCTION
Casey et al. (1988) analyzed the regulation by iron of the TFRC gene by examining mouse cells transformed with chimeric constructs containing the human transferrin receptor gene's promoter and either the structural gene for bacterial chloramphenicol acetyltransferase or the human TFRC cDNA. They concluded that at least 2 genetic elements, one 5-prime and one 3-prime to the gene, are involved in the regulation of the TFRC gene by iron. Radoshitzky et al. (2007) demonstrated a specific high-affinity association between TFR1 and the entry glycoprotein of Machupo virus (a New World arenavirus). Expression of human TFR1, but not human TFR2 (604720), in hamster cell lines markedly enhanced the infection of viruses pseudotyped with the glycoprotein of Machupo, Guanarito, and Junin viruses, but not with those of Lassa or lymphocytic choriomeningitis viruses. An anti-TFR1 antibody efficiently inhibited the replication of Machupo, Guanarito, Junin, and Sabia viruses, but not that of Lassa virus. Iron depletion of culture medium enhanced, and iron supplementation decreased, the efficiency of infection by Junin and Machupo but not Lassa pseudoviruses. Radoshitzky et al. (2007) concluded that TFR1 is a cellular receptor for New World hemorrhagic fever arenaviruses. Ishii et al. (2009) found that knockdown of Ppargc1b (608886) in primary mouse osteoclasts impaired their differentiation and mitochondrial biogenesis. Transferrin receptor expression was induced in osteoclasts via iron regulatory protein-2 (IREB2; 147582), and Tfrc-mediated iron uptake promoted osteoclast differentiation and bone-resorbing activity, which was associated with the induction of mitochondrial respiration, production of reactive oxygen species, and accelerated Ppargc1b transcription. Iron chelation inhibited osteoclastic bone resorption and protected female mice against bone loss following estrogen deficiency resulting from ovariectomy. Ishii et al. (2009) concluded that mitochondrial biogenesis, which is induced by PPARGC1B and supported by TFRC-mediated iron uptake for utilization by mitochondrial respiratory proteins, is fundamental to osteoclast activation and bone metabolism. Elahi et al. (2013) showed that physiologically enriched CD71+ erythroid cells in neonatal mice and human cord blood have distinctive immunosuppressive properties. The production of innate immune protective cytokines by adult cells is diminished after transfer to neonatal mice or after coculture with neonatal splenocytes. Neonatal CD7 ... More on the omim web site
Aug. 24, 2020: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 190010 was added.
Jan. 28, 2016: Protein entry updated
Automatic update: model status changed
Jan. 25, 2016: Protein entry updated
Automatic update: model status changed