Absence of Binding Between the Human Transferrin Receptor and the Transferrin Complex of Biological Toxic Trace Element, Aluminum, Because of an Incomplete Open/Closed Form of the Complex

Abstract

Human transferrin (Tf) very tightly binds two ferric ions to deliver iron to cells. Fe(III)(2)Tf (Fe(2)Tf) binds to the Tf receptor (TfR) at pH 7.4; however, iron-free Tf (apoTf) does not. Iron uptake is facilitated by endocytosis of the Fe(2)Tf-TfR complex. Tf can also bind aluminum ions, which cause toxic effects and are associated with many diseases. Since Al(III)(2)Tf (Al(2)Tf) does not bind to TfR, the uptake of aluminum by the cells does not occur through a TfR-mediated pathway. We have studied the absence of binding between Al(2)Tf and TfR by investigating the physicochemical characteristics of apoTf, Al(2)Tf, Fe(2)Tf, and TfR. The hydrodynamic radius of 38.8 A for Al(2)Tf obtained by dynamic light scattering was between that of 42.6 A for apoTf and 37.2 A for Fe(2)Tf. The zeta potential of -11.3 mV for Al(2)Tf measured by capillary electrophoresis was close to -11.2 mV for apoTf as compared to -11.9 mV for Fe(2)Tf, indicating that the Al(2)Tf surface had a relatively scarce negative charge as the apoTf surface had. These results demonstrated that the structure of Al(2)Tf was a trade-off between the closed and open forms of Fe(2)Tf and apoTf, respectively. Consequently, it is suggested that Al(2)Tf cannot form specific ionic interresidual interactions, such as those formed by Fe(2)Tf, to bind to TfR, resulting in impossible complex formation between Al(2)Tf and TfR.

Dynamic loading of immature epiphyseal cartilage pumps nutrients out of vascular canals

“…This dependency was similarly observed in loaded hydrogels (Albro et al, 2008) and was expected since larger solutes exchange momentum more effectively with a deforming solid matrix due to increased hindrance (Mauck et al, 2003). Transferrin (80 kDa) concentration was enhanced less than the 70 kDa dextran, possibly due to the smaller hydrodynamic radius and reduced hindrance of this compact globular protein (4.3 nm for transferrin (Sakajiri et al, 2009) versus 7.4 nm for 70 kDa dextran, Lebrun and Junter, 1993). Since the enhancement of transferrin was similar to that of the smaller 10 kDa dextran (2.7 nm, Lebrun and Junter, 1993), other factors may play a role as well.…”

The binding, transport and fate of aluminium in biological cells

“…A c c e p t e d M a n u s c r i p t route of uptake for iron as, additionally a mechanism of uptake of aluminium is complicated by evidence that not all transferrin-aluminium complexes are bound by all transferrin receptors [28,29] and that any aluminium-transferrin-receptor complex which might be taken up by endocytosis is unlikely to be metabolised further due to the distinct differences in redox chemistry between iron (III) and aluminium (III) [30].…”

Aluminum and Alzheimer's Disease: After a Century of Controversy, Is there a Plausible Link?

“…4) [27,68,175]. Most notably, recent research evidence shows that Al-transferrin complexes are not bound by the TfR [198][199][200] because of an incomplete open/closed form which precludes them from forming specific ionic inter-residual interactions, such as those formed by iron-transferrin and the TfR [198]. This implies that Al-transferrin transfer from the blood stream to cytoplasm may not follow the classical iron-TfR acquisition pathway.…”