The glycation site specificity of human serum transferrin is a determinant for transferrin's functional impairment under elevated glycaemic conditions

• Type: Article in International Scientific Journal
• Date: 2014

Authors

Andre M N Silva (Author) Other; Paulo R H Sousa (Author) Other; Joao T S Coimbra (Author) Other; Natercia F Bras (Author) Other; Rui Vitorino (Author) Other; Pedro A Fernandes (Author) FCUP; Maria J Ramos (Author) FCUP; Maria Rangel (Author) ICBAS; Pedro Domingues (Author) Other

Journal

Title: Biochemical Journal

Vol. 461

Pages: 33-42

ISSN: 0264-6021

Publisher: PORTLAND PRESS LTD

Indexing

ISI Web of Knowledge - 20 Citations

Scopus - 19 Citations

Other information

Authenticus ID: P-009-JG5

DOI: 10.1042/bj20140133

Abstract (EN): The mechanisms involving iron toxicity in diabetes mellitus are not completely understood. However, the spontaneous reaction of reducing sugars with protein amino groups, known as glycation, has been shown to compromise the action of Tf (transferrin), the systemic iron transporter. In order to understand the structural alterations that impair its function, Tf was glycated in vitro and the modification sites were determined by MS. Iron binding to glycated Tf was assessed and a computational approach was conducted to study how glycation influences the iron-binding capacity of this protein. Glycated Tf samples were found to bind iron less avidly than non-modified Tf and MS results revealed 12 glycation sites, allowing the establishment of Lys(534) and Lys(206) as the most vulnerable residues to this modification. Their increased susceptibility to glycation was found to relate to their low side-chain pK(a) values. Lys(534) and Lys(206) participate in hydrogen bonding crucial for iron stabilization in the C- and N-lobes of the protein respectively, and their modification is bound to influence iron binding. Furthermore, the orientation of the glucose residues at these sites blocks the entrance to the iron-binding pocket. Molecular dynamics simulations also suggested that additional loss of iron binding capacity may result from the stereochemical effects induced by the glycation of lysine residues that prevent the conformational changes (from open to closed Tf forms) required for metal binding. Altogether, the results indicate that Tf is particularly vulnerable to glycation and that this modification targets spots that are particularly relevant to its function.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 10