CD71 TFRC (transferrin receptor)
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 2 glycoprotein
Proliferating Cell
Colon
Brain
Endothelium
95 / 95
190 / 190

Expression
CD71 is expressed at high levels on all proliferating cells.  CD71 expression is very low on resting leukocytes but is upregulated upon activation, presumably reflecting the use of iron.  In other tissues CD71 is expressed on most dividing cells and also on capillary endothelium in the brain.  Cellular distribution reflects the need for iron.  In reticulocytes and erythroid precursors, unlike other cell types, the need for iron and proliferation are not related in erythroid cells, because the need for iron is related to hem synthesis and differentiation rather than proliferation.  There is overexpression in certain tumors such as glioma and colon cancer. 


Structure
MOLECULAR FAMILY NAME: Belongs to the transferrin receptor family.

CD71 is a single-pass type-2 671 aa disulfide-bonded homodimer glycoprotein.  It contains a 671 aa extracellular C-terminal domain which contains a transferrin binding site, 3 N- and 1 O-glycosylation sites, a 28 aa transmembrane domain which contains a cysteine residue in proximal to the cytoplasmic domains which is acylated  and a 61 aa N-terminal cytoplasmic domain containing a conserved 20 aa-23 aa tetrapeptide sequence YTRF essential for mediating rapid endocytosis and recycling.  

MOLECULAR MASS
Cell Type Unreduced Reduced Comment
Proliferating cells 190 kDa 95 kDa
Reticulocytes 190 kDa 95 kDa
Brain capillary endothelium 190 kDa 95 kDa

POST-TRANSCRIPTIONAL MODIFICATION

mRNA has an unusually long 3' untranslated region of about 3 kb which contains stem and loop structures known as iron-regulating elements (IREs), which bind to iron-regulating proteins (IRP-1 and IRP-2), and which stabilize the mRNA.  In iron-replete cells, IRP-1 and IRP2 lose their affinity for CD71 mRNA and/or are degraded and the CD71 mRNA is therefore destabilized and subject to degradation by ribonucleases.  This has the effect of reducing transferrin receptor expression and lowering the uptake of iron to prevent excessive iron uptake, which could be toxic to the cell.  IRP-1 is identical to mitochondrial aconitase.  IRP-2 is homologous to aconitase, but has not yet been shown to have aconitase activity.

POST-TRANSLATIONAL MODIFICATION

There are 3 N-linked glycans and 1 O-linked glycan.  Cysteine close to cytoplasmic face of the transmembrane region is acylated via a thioester bond to palmitic acid.  The functional significance is unknown.  The cytoplasmic tail is phosphorylated by protein kinase C on serine/threonine, but phosphorylation does not seem to be essential for rapid endocytosis.

Ligands
The ligand for CD71 is transferrin, the serum iron-transport protein.  CD71 associates non-covalently with the TCR z chain in T cells, where it may play a role in signal transduction.  CD71 monomers have been reported to form a complex with the integrin CD29/CD49c VLA-3 in some cell lines, via a disulfide bond interaction between CD71 and CD49c.

LIGANDS AND MOLECULES ASSOCIATED WITH CD71
Molecule Comment
Transferrin (ferrotransferrin) Mediates iron transport



Function
CD71 plays a critical role in cell proliferation by controlling the supply of iron, which is essential for many metabolic pathways, through the binding and endocytosis of transferrin, the major iron-carrying protein.  The expression of CD71 is regulated at the post-transcriptional level through the control of mRNA stability and is closely linked to intracellular iron levels.  Upon iron deprivation, a cytoplasmic protein, known as the iron-response element binding protein (IRE-BP), stabilizes CD71 mRNA by binding to specific sequences, IREs, within the 3' untranslated region of the CD71 mRNA.  When iron levels are high, the IRE-BP affinity for IREs is lower and CD71 mRNA is more susceptible to degradation.  Nitric oxide can affect CD71 expression independently of intracellular iron concentration by activating IRE-BP binding to IREs and thus stabilizing CD71 mRNA.  In addition to the role in delivering iron, CD71 may function in the regulation of cell growth (see CD178).  Several CD71 antibodies block transferrin binding and leads to an arrest in cell division and an accumulation of cells in S-phase.

Iron uptake: Ferrotransferrin binds to CD71 at neutral pH and is internalized to an acidic endosomal compartment where the pH is about 5.  Iron is released and transported into cytoplasm by an as yet poorly understood process.  Iron-free apotransferrin remains bound to CD71 at pH5 and is returned to the cell surface, where the pH rises to about 7.4.  At neutral pH, apotransferrin loses its affinity for the receptor and is released into the circulation, allowing a new cycle to begin.

BIOCHEMICAL ACTIVITY

CD71 binds transferrin and hence mediates an uptake of iron.  The uptake of iron has been used as a target for antibodies to inhibit proliferation and also to target cytotoxic molecules to proliferating cells.  The transferrin receptor has also been used to transfect DNA into cells, "transferrinfection". 

DISEASE RELEVANCE AND FUNCTION OF CD71 IN INTACT ANIMAL

CD71 can bind IgA complexes and is implicated in IgA nephropathy by mediating IgA1-complex deposition in glomerular mesangia.



Comments
Proteins that share sequence homology with CD71 have not previously been described.  However it has been noted that a 55 aa sequence with residues Phe237-Ile290 shares a 43.6% identity with a region of streptococcal C5a peptidase with residues Tyr371-Ile425.  The ALIGN score for this comparison is 9.33 standard deviations, making the similarity highly significant.

MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD71

Elements of CD71 are transactivated by Ets-1 and probably Sp1.  MafB, and AP-1 like protein, interacts with Ets-1 and downregulates the transferrin receptor gene.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD71: No information.

ADDITIONAL INSIGHTS

The N-terminal intracellular domain mediates rapid endocytosis and recycling.  The critical feature for endocytosis seems to be located in a highly conserved tetrapeptide YTRF, with a tyrosine located in a tight turn. The proteins interacting with the cytoplasmic tail that mediate rapid endocytosis are still not completely identified.  Transferrin receptors of human, mouse, rat, Chinese hamster and chicken all possess a highly conserved RGD sequence flanked by hydrophobic residues.  The significance of this for transferrin binding or other functions is currently unknown, but it could suggest an evolutionary link with cell adhesion molecules. Insects have been shown to have a transferrin-related molecule, which suggests that they might have transferrin receptors.  A region of the transferrin receptor from Phe237 to Ile290 is 44% identical to a region of streptococcal C5a peptidase.  The human type II ecto-enzyme N-acetylated a -linked acid dipeptidase, also known as prostate-specific membrane antigen, although it is not prostate-specific, shows a significant homology to the transferrin receptor.

Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 7037P02786
MouseS29548X57349
RatA34549M58040
Antibodies
DF1513   View Reactivity

Revised June 25, 2008


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