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.
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.
Structure and Function
Molecular Architecture
TFR2 is a type II transmembrane glycoprotein composed of[@kawabata1999]:
801 amino acids in humans
Large extracellular domain: Contains the transferrin-binding site
Single transmembrane domain: Anchors the protein to the membrane
Short cytoplasmic tail: Contains internalization signals
TFR2 shares approximately 45% sequence homology with TFR1 but has distinct functional properties[@west2000].
Transferrin Binding
TFR2 binds holo-transferrin (iron-loaded [transferrin](/proteins/transferrin-protein)) with lower affinity than TFR1[@kawabata2004]:
TFR1: Kd ~1 nM (high affinity)
TFR2: Kd ~30 nM (lower affinity)
This difference allows TFR2 to function as an iron sensor
Only activates at higher transferrin saturation levels
Iron Sensing Function
TFR2 acts as a sensor of systemic iron status[@gao2013]:
Holo-transferrin binding: Occurs when circulating iron is high
[Kawabata H et al, Molecular cloning of transferrin receptor 2 (1999)](https://pubmed.ncbi.nlm.nih.gov/10636724/)
[West AP et al, Structure of transferrin receptor 2 and implications for hemochromatosis (2000)](https://pubmed.ncbi.nlm.nih.gov/11162978/)
[Kawabata H et al, Expression of transferrin receptor 2 in normal and neoplastic hematopoietic cells (2004)](https://pubmed.ncbi.nlm.nih.gov/15201106/)
[Gao J et al, Transferrin receptor 2: a new player in iron sensing and hemochromatosis (2013)](https://pubmed.ncbi.nlm.nih.gov/23719327/)
[Wallace DF et al, Combined deletion of Hfe and transferrin receptor 2 in mice leads to marked dysregulation of hepcidin and iron overload (2007)](https://pubmed.ncbi.nlm.nih.gov/17959927/)
[Camaschella C et al, The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22 (2000)](https://pubmed.ncbi.nlm.nih.gov/10854245/)
[Ke Y et al, Age-dependent and iron-independent localization of iron regulatory proteins 1 and 2 in the brains of Belgrade rats (2006)](https://pubmed.ncbi.nlm.nih.gov/16473185/)
[Rouault TA, Iron metabolism in the central nervous system and neurodegenerative disorders (2013)](https://pubmed.ncbi.nlm.nih.gov/23719329/)
[Raha AA et al, Hepcidin, ferroportin and brain iron homeostasis (2013)](https://pubmed.ncbi.nlm.nih.gov/24424461/)
[Ayton S et al, Brain iron is associated with accelerated cognitive decline in people with Alzheimer pathology (2018)](https://pubmed.ncbi.nlm.nih.gov/28842895/)
[Sturm B et al, Transferrin receptor 2 gene polymorphisms and clinical findings in Friedreich ataxia (2015)](https://pubmed.ncbi.nlm.nih.gov/25406230/)
[Wallace DF, Subramaniam N, The role of transferrin receptor 2 in iron sensing and hemochromatosis (2017)](https://pubmed.ncbi.nlm.nih.gov/28852068/)
[Nandar W, Connor JR, Ferroportin and iron regulation in neurodegeneration (2019)](https://pubmed.ncbi.nlm.nih.gov/30987100/)
[Gammella E et al, Iron and neurodegeneration: the ferroptosis connection (2021)](https://pubmed.ncbi.nlm.nih.gov/34358492/)