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Structural basis of multivalent galactose-based dendrimer recognition by human galectin-7.

Significance Statement

Galectins are a family of lectins which is highly conserved and ubiquitously found in the animal kingdom. They present high specificity for for β-galactose-containing oligosaccharides. Currently, 15 galectins have been identified in mammals and are involved in a wide range of physiological events including cell-cell and cell-matrix interactions, highlighting their significance in signal transduction and other cellular mechanisms. Human galectin-7 is a proto type galectin readily forming dimer and is implicated in the progression of tumour growth. Galectins in general have been shown to produce lattices at the cell surface through cross-linking that can activate signalling pathways triggering the immune response following host–pathogen interactions and activation of immune cells. Glycodendrimers are a class of polyvalent dendrimers that include carbohydrate groups and show great flexibility, making them unique nanodevices for biochemical applications. Furthermore, the binding of glycodendrimers with lectins is usually enhanced compared with single monosaccharides in a phenomenon described as “cluster glycoside effect”. This study aimed at understanding this effect at the molecular level which should eventually lead to create carbohydrate structures with enhanced selectivity and affinity towards specific target lectins. A library of synthetic galactose-based dendrimeric units, or dendrons, of varying size and composition were created and utilised to explore the cross-linking of human galectin-7 through carbohydrate recognition to form supramolecular assemblies. These compounds were fashioned based on a modular approach, making use of “click chemistry” protocols, with an array of core groups, branching units and terminal moieties combined together. This study presents the molecular mechanisms underlying the recognition of carbohydrate-based dendrons by a human lectin using high-resolution X-ray crystallography and will help in designing new tools to refine our understanding of carbohydrates identification by lectins.

Figure Legend: Single galactose-dendrimer binding to multiple human galectin-7 molecules, crystal structure (PDB 4UW5) and schematic of binding.

Structural basis of multivalent galactose-based dendrimer recognition by human galectin-7

 

 

 

 

 

 

 

 

 

 

 

 

Journal Reference

Ramaswamy S1 , Sleiman MH2, Masuyer G1, Arbez-Gindre C2, Micha-Screttas M2, Calogeropoulou T2, Steele BR2, Acharya KR1. FEBS J. 2015 ;282(2):372-87.

  1. Department of Biology and Biochemistry, University of Bath, UK.
  2. Institute of Biology, Medicinal Chemistry & Biotechnology, National Hellenic Research Foundation, Athens, Greece.

Abstract

Galectins are evolutionarily conserved and ubiquitously present animal lectins with a high affinity for β-galactose-containing oligosaccharides. To date, 15 mammalian galectins have been identified. Their involvement in cell-cell and cell-matrix interactions has highlighted their importance in signal transduction and other intracellular processes. Human galectin-7 (hGal-7) is a 15 kDa proto type galectin that forms a dimer in solution and its involvement in the stimulation and development of tumour growth has been reported. Previously, we reported the crystal structure of hGal-7 and its complex with galactose and lactose which provided insight into its molecular recognition and detailed interactions. Here, we present newly obtained high-resolution structural data on carbohydrate-based dendrons in complex with hGal-7. Our crystallographic data reveal how multivalent ligands interact with and form cross-links with these galectin molecules. Understanding how these dendrimeric compounds interact with hGal-7 would help in the design of new tools to investigate the recognition of carbohydrates by lectins.

© 2014 FEBS.

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