Structural and Molecular Basis of Carbohydrate-Protein Interaction Systems as Potential Therapeutic Targets

Yukiko      Kamiya; Maho      Yagi-Utsumi; Hirokazu      Yagi; Koichi      Kato

doi:10.2174/138161211796355074

Abstract

The sugar chains covalently modifying proteins and lipids are recognized by a variety of proteins, thereby mediating a broad range of physiological and pathological events on cell surfaces as well as in cells. Hence, these carbohydrate – protein interaction systems could be potential therapeutic targets for various diseases, including viral infections, autoimmune diseases and neurodegenerative disorders. Cumulative crystallographic data of lectins complexed with their cognate carbohydrate ligands have elucidated the sugar recognition modes of these proteins, offering a structural basis for the design of drugs targeting carbohydrate – lectin interaction systems. In particular, structural and functional studies of animal L-type lectins, which possess a carbohydrate recognition domain with a structural resemblance to that of leguminous lectins such as concanavalin A, have demonstrated the molecular mechanisms underlying their distinct roles in sorting and trafficking of glycoproteins in cells, exemplifying the structure-based engineering that manipulates the sugar-binding properties of lectins. Furthermore, structural basis has been provided for the functional interplay between the L-type lectin ERGIC-53 and the EF-hand Ca2+-binding protein MCFD2 in the intracellular transport of the coagulation factors V and VIII. This article also deals with pathological carbohydrate – protein interactions involving ganglioside clusters on cell surfaces, particularly focusing on the interaction between amyloid β (Aβ) and GM1 ganglioside. This interaction triggers conformational transition and consequent aggregation of Aβ, and therefore, is considered to be a key step in Alzheimer's disease. The recently reported structural information of the Aβ – GM1 interaction is presented, underscoring the significance of assemblages of glycoconjugates as therapeutic targets.

Keywords: carbohydrate, –, protein interaction, lectin, gangliosid, hemagglutinin, amyloid β, X-ray crystallography, NMR spectroscopy, frontal affinity chromatography, ganglioside, neurodegenerative, concanavalin, glycoconjugates, thermostability, glycosylation, leucocytes, molecular chaperones, Dysfunction, topology, jacalin, Epidermal Growth Factor Receptor, Minimum Inhibitory Concentrations, Human Breast Adenocarcinoma, 3-(4, 5-Dimethyl-2-Thiazyl)-2, 5-Diphenyl-2H-Tetrazolium Bromide, Dimethyl Sulfoxide, Mueller-Hinton, Phosphate Buffered Saline, Enzymelinked Immunosorbentassy, Tlomere Rpeat Aplification Potocol