Abstract
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.
Highlights
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For apo-Tf there are no major differences observed, holo-Tf shows a predominant population of a partially open conformation, besides the open and closed conformations, as evidenced by the radius of gyration (Rg) and Dmax values for the three-state model at all pH values (Figure 3). These results show that holo-Tf is more elongated and flexible than the apo-form, suggesting that the presence of iron has an impact on the stability of transferrin in the solution
Static snapshots that we attempted to derive from X-ray diffraction data were hampered by intrinsically low crystal quality and/or high sensitivity to crystal manipulation
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Human serum transferrin (Tf), known as serotransferrin, is a ~80 kDa glycoprotein that transits blood plasma, whose function is to maintain iron homeostasis by transporting iron from its absorption site to every cell through the blood vessels. Its structure consists of two homologous lobes, an N-terminal lobe and a C-terminal lobe, each subdivided into two domains, in between which a metal-binding site is found, allowing Tf to bind two ferric ions per molecule [1,2]. The transferrin completes a cycle in which it transits the bloodstream as holo-Tf (iron-loaded form) and binds to the transferrin receptor (TfR)
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