AN INTEGRATED COMPUTATIONAL ANALYSIS OF THE STRUCTURE, DYNAMICS AND LIGAND-BINDING INTERACTIONS OF THE HUMAN GALECTIN NETWORK

GUARDIA, CARLOS; GAUTO DIEGO ; DI LELLA SANTIAGO; RABINOVICH GABRIEL; MARTÍ MARCELO; ESTRIN DARIO

JOURNAL OF CHEMICAL INFORMATION AND MODELING

AMER CHEMICAL SOC

Lugar: Philadelphia; Año: 2011 vol. 51 p. 1918 - 1939

1549-9596

Multivalent lectin-glycan lattices represent a mean of molecular recognition which organisms can use to decode the biological information present in their own ‘glycome’. Galectins, a family of evolutionarily conserved animal lectins, have been shown to modulate signaling processes leading to inflammation, apoptosis, immunoregulation and angiogenesis, through their ability to interact with poly-N-acetyllactosamine-enriched glycoconjugates. To date 16 human galectins carbohydrate recognition domains have been established by sequence analysis and found to be expressed in several tissues. Given the divergent functions of these lectins and their selective involvement in physiological and pathological processes, it is of vital importance to understand common and differential features in order to search for specific inhibitors of individual members of the human galectin family. To achieve this goal, a biochemical comparison of the structure-function relationship of these glycan-binding proteins is required. Seeking for structural differences that might explain divergent biological functions, here we performed an integrated computational analysis of the structure, dynamics and ligand-binding interactions of all individual members of the human galectin family, including galectin-4 and -12 N-terminus, placental protein 13 (PP13) and PP13-like protein for which no experimental structural information is available. Our results show that all galectins adopt the same fold and the carbohydrate recognition domains are very similar with structural differences located in specific loops. These differences are reflected in the dynamics features, where mobility changes translate into entropy values which significantly influence their ligand affinity. Thus, selectivities as well as possible biological roles appear to be modulated by subtle differences in the monosaccharide binding sites (MBS). Taken together, our results may contribute to the understanding, at a molecular level, of the structural and dynamical determinants that distinguish individual human galectins.