TFRC Membrane Protein Introduction

Introduction of TFRC

Transferrin receptor 1 (TFR1 or TFRC), also known as CD71, is a homodimeric protein that is a key regulator of cellular iron homeostasis and proliferation. It is a glycosylated type II transmembrane protein encoded by the TFRC gene and has a molecular weight of 190 kDa. TFR1 is composed of two identical subunits which are linked by two disulfide bridges. Each of the two subunits possesses a transmembrane domain, a cytoplasmic endodomain of about 15 kDa and a soluble ectodomain directed towards the biological fluid. Each of these subunits can interact with one iron-loaded protein. TFR1 is arranged in four domains: the helical, the apical, the protease-like, which is close to the plasma membrane, and the endodomain. TFR1 is ubiquitously expressed in all tissues and is the main receptor that interacts with iron-loaded transferrin (Tf) to import iron into the cell. TFR1 has a high affinity for iron-loaded transferrin at neutral pH, and traffics to the early acidic endosome when binding to a ligand, where it releases iron, recycles back to the cell surface, and releases transferrin.

The Function of TFRC Membrane Protein

TFR1 plays a critical role in iron homeostasis by serving as a gatekeeper regulating iron uptake from Tf. On the cell surface, diferric-transferrin binds to TFR1, and TFR1 initiates internalization of the complex by clathrin-mediated endocytosis. Transferring-bound iron enters cells that require iron in a regulated manner essentially through a TFR1-mediated mechanism. In the state of iron deficiency in cells, TFR1 expression is increased, while in the presence of excess iron, TFR1 expression is decreased. Due to increased iron demand, rapidly proliferating cells and energy-requiring cells, such as malignant cells, osteoclasts and activated lymphocytes, express high levels of TFR1. It is worth noting that the overexpression of TFR1 in malignant cells is associated with poor prognosis of cancer. TFR1 has been shown to mediate NF-kB signaling in malignant cells via the interaction with the inhibitor of the NF-kB kinase complex, thereby increasing cancer cell survival. In addition, TFR1 can contribute to mitochondrial respiration and the production of reactive oxygen species (ROS), which play important roles in tumor growth. Overexpression of TFR1 on malignant cells and its central role in cancer cell pathology make it a significant target for antibody-mediated cancer therapy.

Fig.1 X-ray crystal structure of the extracellular domain of TfR1. The ribbon diagram of the dimeric TfR1 has a butterfly-like shape. The TfR1 monomer contains three distinct domains. In one of the monomers, the protease-like, apical and helical domains are represented by red, green and yellow, respectively, while the other monomer is blue. Stem area is shown in gray and attached to the transmembrane helix. (Qian, 2002)

Application of TFRC Membrane Protein Literature

1. Kawabata H. Transferrin and Transferrin Receptors Update. Free Radical Biology & Medicine. 2018, 133:46-54. PubMed ID: 29969719
   
   

   This review updates and summarizes the knowledge of mammalian transferrin and its receptors.

2. Gruszczyk J., et al. Transferrin receptor 1 is a reticulocyte-specific receptor for Plasmodium vivax. Science. 2018, 359(6371):48-55. PubMed ID: 29302006
   
   

   This article identifies that transferrin receptor 1 (TfR1) is a receptor for Plasmodium vivax reticulum-binding protein 2b (PvRBP2b).

3. Rosager A.M., et al. Transferrin receptor-1 and ferritin heavy and light chains in astrocytic brain tumors: Expression and prognostic value. Plos One. 2017, 12(8):e0182954. PubMed ID: 28837569
   
   

   This study investigates the expression and prognostic value of transferrin receptor-1 (TfR1) and ferritin heavy (FTH) and light (FTL) chains in astrocytic brain tumors.

4. Jamnongkan W., et al. Upregulation of transferrin receptor-1 induces cholangiocarcinoma progression via induction of labile iron pool. Tumour Biol. 2017, 39(7): 1010428317717655. PubMed ID: 28671021
   
   

   This article shows that iron uptake caused by high expression of transferrin receptor-1 contributes to an increase in the labile iron pool which plays an important role in the progression of cholangiocarcinoma.

5. Li H., et al. Decreasing TfR1 expression reverses anemia and hepcidin suppression in β-thalassemic mice. Blood. 2017, 129(11):1514-1526. PubMed ID: 28151426
   
   

   This study reveals that decreasing TfR1 expression reduces ineffective erythropoiesis and provides an endogenous mechanism to upregulate hepcidin, leading to sustained iron-restricted erythropoiesis and preventing systemic iron overload in β-thalassemic mice.

TFRC Preparation Options

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Reference

1. Qian Z M, et al. (2002). Targeted drug delivery via the transferrin receptor-mediated endocytosis pathway. Pharmacological reviews. 54(4):561.

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