| 9.B.229. The Transferrin Receptor, CD71, (TFR) Family
Cellular
uptake of iron occurs via receptor-mediated endocytosis of
ligand-occupied transferrin receptors (TFR; TrR; CD71) 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. TrR is necessary for
development of erythrocytes and the nervous system. A
second ligand, the heditary hemochromatosis protein HFE, competes for
binding with transferrin for an overlapping C-terminal binding site. It positively regulates T and B cell proliferation through iron uptake
(Jabara et al. 2016). TrR acts as a receptor for new-world arenaviruses: Guanarito, Junin and Machupo viruses (Radoshitzky et al. 2008).
TFR1 mediates cellular iron uptake through clathrin-dependent endocytosis of iron-loaded transferrin. Since the number of TFR1
molecules at the cell surface is the rate-limiting step for iron entry
into cells and is essential to prevent iron overload, TFR1 expression is
precisely controlled at multiple levels. The latest advances in the molecular regulation of
TFR1 expression and an understanding of TFR1
function beyond its canonical role in providing iron for erythroid
precursors and rapidly proliferating cells has been reviewed (Gammella et al. 2017). Regulation of transferrin receptor trafficking by optineurin and its disease-associated mutants hsas been reviewed (Moharir et al. 2023).
The yeast manganese transporter, Smf1, is subject to two levels of regulation: heavy metal-induced sequestration in the cell and ubiquitination and degradation in the vacuole. Degradation requires Bsd2, a membrane protein with a PPxY motif that recruits the ubiquitin ligase Rsp5, and which plays a role in the quality control of membrane proteins that expose hydrophilic residues to the lipid bilayer. Stimpson et al. 2006 showed that degradation of Smf1 requires in addition one of a pair of related yeast proteins, Tre1 and Tre2, that also contain PPxY motifs. Tre1 can partially inhibit manganese uptake without Bsd2, but Bsd2 is required to induce Smf1 degradation. It has a relatively hydrophilic transmembrane domain and binds to Bsd2. Possibly, the Tre proteins specifically link Smf1 to the Bsd2-dependent quality control system. Their luminal domains are related to the transferrin receptor, but these are dispensable for Smf1 regulation (Stimpson et al. 2006).
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| References: |
Gammella, E., P. Buratti, G. Cairo, and S. Recalcati. (2017). The transferrin receptor: the cellular iron gate. Metallomics. [Epub: Ahead of Print]
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Jabara, H.H., S.E. Boyden, J. Chou, N. Ramesh, M.J. Massaad, H. Benson, W. Bainter, D. Fraulino, F. Rahimov, C. Sieff, Z.J. Liu, S.H. Alshemmari, B.K. Al-Ramadi, H. Al-Dhekri, R. Arnaout, M. Abu-Shukair, A. Vatsayan, E. Silver, S. Ahuja, E.G. Davies, M. Sola-Visner, T.K. Ohsumi, N.C. Andrews, L.D. Notarangelo, M.D. Fleming, W. Al-Herz, L.M. Kunkel, and R.S. Geha. (2016). A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. Nat. Genet. 48: 74-78.
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Kawabata, H., S. Sakamoto, T. Masuda, T. Uchiyama, K. Ohmori, H.P. Koeffler, and A. Takaori-Kondo. (2016). Roles of transferrin receptors in erythropoiesis. Rinsho Ketsueki 57: 951-958.
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Mesters, J.R., C. Barinka, W. Li, T. Tsukamoto, P. Majer, B.S. Slusher, J. Konvalinka, and R. Hilgenfeld. (2006). Structure of glutamate carboxypeptidase II, a drug target in neuronal damage and prostate cancer. EMBO. J. 25: 1375-1384.
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Moharir, S.C., K. Sirohi, and G. Swarup. (2023). Regulation of transferrin receptor trafficking by optineurin and its disease-associated mutants. Prog Mol Biol Transl Sci 194: 67-78.
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Radoshitzky, S.R., J.H. Kuhn, C.F. Spiropoulou, C.G. Albariño, D.P. Nguyen, J. Salazar-Bravo, T. Dorfman, A.S. Lee, E. Wang, S.R. Ross, H. Choe, and M. Farzan. (2008). Receptor determinants of zoonotic transmission of New World hemorrhagic fever arenaviruses. Proc. Natl. Acad. Sci. USA 105: 2664-2669.
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Recalcati, S., E. Gammella, P. Buratti, and G. Cairo. (2017). Molecular regulation of cellular iron balance. IUBMB Life 69: 389-398.
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Stimpson, H.E., M.J. Lewis, and H.R. Pelham. (2006). Transferrin receptor-like proteins control the degradation of a yeast metal transporter. EMBO. J. 25: 662-672.
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Tsuji, Y. (2020). Transmembrane protein western blotting: Impact of sample preparation on detection of SLC11A2 (DMT1) and SLC40A1 (ferroportin). PLoS One 15: e0235563.
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Varga, L., Z. Besenyi, V.R. Paczona, I. Farkas, S. Urbán, G. Sipka, L. Pávics, Z. Varga, E. Fodor, K. Hideghéty, J. Olah, Z. Bajory, and A. Maráz. (2023). Prostate-specific membrane antigen-based imaging for stereotactic irradiation of low-volume progressive prostate cancer: a single-center experience. Front Oncol 13: 1166665.
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 9.B.229.1.1 | The transferrin receptor, TfR or TFRC, of 760 aas and 1 TMS (Recalcati et al. 2017). Optimal conditions for Western blotting for this and other proteins requires that the sample not be boiled (Tsuji 2020). | | TfR of Homo sapiens |
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| 9.B.229.1.2 | Transferrin receptor-2, TfR2 or TFR2 of 801 aas and 1 TMS. TFR2, is predominantly expressed in hepatocytes and erythroid precursor cells. In the liver, TFR2 forms a complex with HFE, a hereditary hemochromatosis-associated
protein, and acts as an iron sensor. In mice, hepatocyte-specific
knockout of the TFR2 gene has been shown to cause systemic iron-overload with decreased
expression of hepcidin, the central regulator of iron homeostasis. In
erythroid cells, TFR2 forms a complex with the erythropoietin receptor and facilitates its
trafficking to the cell membrane. Hematopoietic cell-specific
knockout of the TFR2 gene causes microcytic erythrocytosis in mice (Kawabata et al. 2016). Hereditary hemochromatosis (HH), also known as ferroportin disease, is caused by mutations in the SLC4OA1 gene. Ferroportin is an iron transmembrane transport protein, and Type 4 HH is the only known form of hemochromatosis that can be inherited in an autosomal dominant fashion (Sonagra AD, Zubair M, 2023, PMiD 37603641).
). | | TFR2 of Homo sapiens |
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| 9.B.229.1.3 | PA domain protein of 891 aas and 1 TMS. | | PA domain protein of Beauveria bassiana (White muscardine disease fungus) (Tritirachium shiotae) |
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| 9.B.229.1.4 | Putative Vacuolar protein sorting-associated protein 70 of 1042 aas and 1 TMS. | | V-S-aP of Glarea lozoyensis |
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| 9.B.229.1.5 | Glutamate carboxypeptidase II of 727 aas and 1 N-terminal TMS.
| | Glutamate carboxypeptidase II of Rhodothermus marinus |
| |
| 9.B.229.1.6 | Transferrin-like receptor protein, Tre1, of 783 aas and 1 (possibly 2 or 3) TMS(s). Tre1 can partially inhibit manganese uptake via Smf1 (TC# 2.A.55.1.1) by itself, but it requires Bsd2 (8.A.30.2.1) to induce Smf1 degradation (Stimpson et al. 2006). | | Tre1 of Saccharomyces cerevisiae |
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| 9.B.229.1.7 | Tre2, a transferrin-like receptor protein of 809 aas and 1 (or mossibly more) TMS(s). May play a role in transport protein degredation via aubiquitin-dependent pathway involving multivesicular body sorting (Stimpson et al. 2006). | | Tre2 of Saccharomymes cerevisiae |
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| 9.B.229.1.8 | FolH1 or prostate-specific membrane antigen (PSMA) of 750 aas and 1 N-terminal TMS, and possibly 1 C-terminal TMS as well. It has both folate hydrolase and
N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) activity with a
preference for tri-alpha-glutamate peptides. It exhibits a dipeptidyl-peptidase IV type activity. In the intestine, it is required
for the uptake of folate. In the brain, it modulates excitatory
neurotransmission through the hydrolysis of the neuropeptide,
N-acylaspartylglutamate (NAAG), thereby releasing glutamate. It is also involved
in prostate tumor progression. It released an unsubstituted, C-terminal glutamyl residue, typically from Ac-Asp-Glu or folylpoly-gamma-glutamates. It binds 2 Zn2+ ions per subunit which is required for NAALADase activity (Mesters et al. 2006). PSMA-based imaging is a promising diagnostic method for specifying the stage and detecting the low-volume progression of prostate cancer (Varga et al. 2023). | | FolH1 or PSMA of Homo sapiens |
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