TCDB is operated by the Saier Lab Bioinformatics Group

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).

References associated with 9.B.229 family:

Gammella, E., P. Buratti, G. Cairo, and S. Recalcati. (2017). The transferrin receptor: the cellular iron gate. Metallomics. [Epub: Ahead of Print] 28671201
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. 26642240
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. 27498743
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. 16467855
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. 36631201
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. 18268337
Recalcati, S., E. Gammella, P. Buratti, and G. Cairo. (2017). Molecular regulation of cellular iron balance. IUBMB Life 69: 389-398. 28480557
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. 16456538
Tsuji, Y. (2020). Transmembrane protein western blotting: Impact of sample preparation on detection of SLC11A2 (DMT1) and SLC40A1 (ferroportin). PLoS One 15: e0235563. 32645092
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. 37637070