Transferrin receptor ligands

It seems clear that complexes 28 and 29 both enter cancer cells by transferrin-mediation. Tumor cells are known to have a high density of transferrin receptors, and this provides a route for the uptake of ruthenium (175). In normal blood plasma, transferrin is only one-third saturated with Fe(III) and therefore vacant sites are available for Ru(III) binding. Baker et al. have shown by X-ray crystallography that complex 29 binds to His-253 of apolactoferrin, one of the Fe(III) ligands in the iron binding cleft of the N-lobe, with displacement of a chloride ligand (176). Ruthenium(III) is well known to have a high affinity for solvent-exposed His side chains of proteins (177). Complex... 

Once in the serum, aluminium can be transported bound to transferrin, and also to albumin and low-molecular ligands such as citrate. However, the transferrrin-aluminium complex will be able to enter cells via the transferrin-transferrin-receptor pathway (see Chapter 8). Within the acidic environment of the endosome, we assume that aluminium would be released from transferrin, but how it exits from this compartment remains unknown. Once in the cytosol of the cell, aluminium is unlikely to be readily incorporated into the iron storage protein ferritin, since this requires redox cycling between Fe2+ and Fe3+ (see Chapter 19). Studies of the subcellular distribution of aluminium in various cell lines and animal models have shown that the majority accumulates in the mitochondria, where it can interfere with calcium homeostasis. Once in the circulation, there seems little doubt that aluminium can cross the blood-brain barrier. 

The process of transcytosis is illustrated in Figure 2.3 for the transferrin receptor (TfR) [37]. The receptor is heavily expressed at the BBB compared to other vascular beds [38]. Transferrin or a monoclonal antibody to the extracellular domain of the receptor protein will bind from the luminal side of the BBB. This triggers cellular uptake by the mechanism of receptor-mediated endocytosis, i.e. the invagination and budding off of parts of the cell membrane as a result of the formation of small vesicles (endosomes). The transceUular passage of ligand (transcytosis) is completed by exocytosis at the abluminal membrane, and the whole process is completed within minutes in vivo. 

Cheng, P. W. Receptor ligand-facilitated gene transfer Enhancement of liposome-mediated gene transfer and expression by transferrin. Hum. Gene Ther. 7 275—282, 1996. 

Pan, B.T and Johnstone, R. (1984) Selective extemalization of the transferrin receptor by sheep reticulocytes in vitro. Response to ligands andinhibitors of endocytosis. J. Biol. Chem. 259,9776-9782. 

Zastrow MV, Kobilka BK (1992) Ligand-regulated internalization and recycling of human j02-adrenergic receptors between the plasma membrane and endosomes containing transferrin receptors. J Biol Chem 267 3530-3538... 

An exception to the general theme of pH-dependent receptor-ligand dissociation in the late endosome occurs in the endocytic pathway that delivers transferrin-bound Iron to cells. A major glycoprotein in the blood, transferrin transports Iron to all tissue cells from the liver (the main site of iron... 

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