Transferrin Receptor 2 is a protein. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
Transferrin receptor 2 (TFR2) is a transmembrane protein that mediates cellular iron uptake and plays a critical role in systemic iron homeostasis. Unlike the ubiquitously expressed transferrin receptor 1 (TFR1), TFR2 has a more restricted tissue distribution and serves primarily as an iron sensor that regulates hepcidin expression.
TFR2 is a type II transmembrane glycoprotein composed of[1]:
TFR2 shares approximately 45% sequence homology with TFR1 but has distinct functional properties[2].
TFR2 binds holo-transferrin (iron-loaded transferrin) with lower affinity than TFR1[3]:
TFR2 acts as a sensor of systemic iron status[4]:
TFR2 is predominantly expressed in hepatocytes and is essential for hepcidin regulation[5]:
Mutations in TFR2 cause hereditary hemochromatosis type 3[6]:
TFR2 is expressed in the brain, including[7]:
TFR2 contributes to brain iron regulation[8]:
In Alzheimer's disease, altered TFR2 expression has been reported[9]:
TFR2 polymorphisms have been studied in Friedreich's ataxia[11]:
| Protein | Interaction | Functional Outcome |
|---|---|---|
| HFE | Complex formation | Iron sensing |
| Transferrin | Ligand binding | Iron uptake |
| Hepcidin | Induced by TFR2 signaling | Iron homeostasis |
| BMP receptors | Co-signaling | SMAD activation |
| Ferroportin | Regulated via hepcidin | Iron export |
Modulating TFR2 signaling may have therapeutic potential[12]:
TFR2 status may predict iron chelation responses[13]:
Current research focuses on[14]:
Kawabata H et al. Molecular cloning of transferrin receptor 2. Journal of Biological Chemistry. 1999. ↩︎
West AP et al. Structure of transferrin receptor 2 and implications for hemochromatosis. Proceedings of the National Academy of Sciences. 2000. ↩︎
Kawabata H et al. Expression of transferrin receptor 2 in normal and neoplastic hematopoietic cells. Blood. 2004. ↩︎
Gao J et al. Transferrin receptor 2: a new player in iron sensing and hemochromatosis. Cell Metabolism. 2013. ↩︎
Wallace DF et al. Combined deletion of Hfe and transferrin receptor 2 in mice leads to marked dysregulation of hepcidin and iron overload. Hepatology. 2007. ↩︎
Camaschella C et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nature Genetics. 2000. ↩︎
Ke Y et al. Age-dependent and iron-independent localization of iron regulatory proteins 1 and 2 in the brains of Belgrade rats. Neuroscience. 2006. ↩︎
Rouault TA. Iron metabolism in the central nervous system and neurodegenerative disorders. Current Opinion in Neurobiology. 2013. ↩︎
Raha AA et al. Hepcidin, ferroportin and brain iron homeostasis. Neurobiology of Disease. 2013. ↩︎
Ayton S et al. Brain iron is associated with accelerated cognitive decline in people with Alzheimer pathology. Molecular Psychiatry. 2018. ↩︎
Sturm B et al. Transferrin receptor 2 gene polymorphisms and clinical findings in Friedreich ataxia. Acta Neurologica Scandinavica. 2015. ↩︎
Wallace DF, Subramaniam N. The role of transferrin receptor 2 in iron sensing and hemochromatosis. Hepatology. 2017. ↩︎
Nandar W, Connor JR. Ferroportin and iron regulation in neurodegeneration. Neurobiology of Disease. 2019. ↩︎
Gammella E et al. Iron and neurodegeneration: the ferroptosis connection. International Journal of Molecular Sciences. 2021. ↩︎