X-ray Characterization of Conformational Changes of Human Apo- and Holo-Transferrin.

Human serum transferrin (Tf) is a bilobed glycoprotein whose function is to transport iron through receptor-mediated endocytosis. The mechanism for iron release is pH-dependent and involves conformational changes in the protein, thus making it an attractive system for possible biomedical applications. In this contribution, two powerful X-ray techniques, namely Macromolecular X-ray Crystallography (MX) and Small Angle X-ray Scattering (SAXS), were used to study the conformational changes of iron-free (apo) and iron-loaded (holo) transferrin in crystal and solution states, respectively, at three different pH values of physiological relevance. A crystallographic model of glycosylated apo-Tf was obtained at 3.0 Å resolution, which did not resolve further despite many efforts to improve crystal quality. In the solution, apo-Tf remained mostly globular in all the pH conditions tested; however, the co-existence of closed, partially open, and open conformations was observed for holo-Tf, which showed a more elongated and flexible shape overall.

The role of transferrins and iron-related proteins in brain iron transport: applications to neurological diseases.

Iron transport in the central nervous system (CNS) is a highly regulated process in which several important proteins participate to ensure this important metal reaches its sites of action. However, iron accumulation has been shown to be a common factor in different neurological disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Multiple Sclerosis, and Sanfilippo syndrome. This review is divided into four parts. The first part describes brain iron transport in homeostasis, mentioning the main proteins involved, whereas the second part contrasts the consequences of iron dysregulation, elaborating on its role in the aforementioned neurodegenerative diseases. The third part details the functions of the main proteins involved in brain iron homeostasis and their role in neurodegeneration. In the fourth part, in order to highlight the importance of transport proteins, the focus is set on human serum transferrin, the main iron transport protein. This final part describes perspectives about the mechanisms and chemical properties of human transferrin for the development of potential targeted drug delivery systems across the blood-brain barrier (BBB) or enhancers for the treatment of neurological diseases.