A distinctive histidine residue is essential for in vivo glycation-inactivation of human CD59 transgenically expressed in mice erythrocytes: Implications for human diabetes complications

5 years ago

A distinctive histidine residue is essential for in vivo glycation-inactivation of human CD59 transgenically expressed in mice erythrocytes: Implications for human diabetes complications

Jose A Halperin, Pamela Ghosh, Rupam Sahoo, Michael Chorev

Clinical and experimental evidences support a link between the complement system and the pathogenesis of diabetes complications. CD59, an extracellular cell membrane-anchored protein, inhibits formation of the membrane attack complex (MAC), the main effector of complement-mediated tissue damage. This complement regulatory activity of human CD59 (hCD59) is inhibited by hyperglycemia-induced ε-amino glycation of Lys41. Biochemical and structural analyses of glycated proteins with known three-dimensional structure revealed that glycation of ε-amino lysyl residues occurs predominantly at “glycation motives” that include lysyl/lysyl pairs or proximity of a histidyl residue, in which the imidazolyl moiety is ≈ 5Å from the ε-amino group. hCD59 contains a distinctive Lys41/His44 putative glycation motif within its active site. In a model of transgenic diabetic mice expressing in erythrocytes either the wild type or a H44Q mutant form of hCD59, we demonstrate in vivo that the His44 is required for Lys41 glycation and consequent functional inactivation of hCD59, as evidenced using a mouse erythrocytes hemolytic assay. Since 1) the His44 residue is not present in CD59 form other animal species and 2) humans are particularly prone to develop complications of diabetes, our results indicate that the Lys41/His44 glycation motif in human CD59 may confer humans a higher risk of developing vascular disease in response to hyperglycemia. This article is protected by copyright. All rights reserved.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/ajh.24886