Transferrin Receptors in the Central Nervous System

Transferrin (Tf), a glycoprotein of 79.5 kDa, contains two homologous iron-binding domains, each of which binds one Fe3+. Transferrin transports iron in the blood stream and delivers it to various tissues, after binding to a specific receptor (TfR) on the cell surface. After binding to specific cell surface receptors, the ligands follow two different pathways: (1) some are degraded within the cells after dissociation from the receptors and (2) others are not degraded but exocytosed intact into the extracellular space. This is the fate of Tf that leaves the iron within the cells in endocytosed vesicles and, as apotransferrin, comes back to the membrane. The intracellular Tf cycle is strictly pH dependent and can be divided into four stages: (1) iron-loaded Tf binds with high affinity to its receptor, (2) the receptor–Tf complex (Tf–TfR) is internalized via coated vesicles, (3) the Tf–TfR complex is exposed to a low pH within the lysosome, which allows the release of iron from Tf while Tf remains bound to its receptor, and (4) finally when the Tf-TfR complex reaches the external membrane, Tf dissociates from its receptor at neutral pH and is released into the circulation as an intact, iron-free protein, apotransferrin.