Abstract
Galectins are proteins involved in diverse cellular contexts due to their capacity to decipher and respond to the information encoded by β-galactoside sugars. In particular, human galectin-4, normally expressed in the healthy gastrointestinal tract, displays differential expression in cancerous tissues and is considered a potential drug target for liver and lung cancer. Galectin-4 is a tandem-repeat galectin characterized by two carbohydrate recognition domains connected by a linker-peptide. Despite their relevance to cell function and pathogenesis, structural characterization of full-length tandem-repeat galectins has remained elusive. Here, we investigate galectin-4 using X-ray crystallography, small- and wide-angle X-ray scattering, molecular modelling, molecular dynamics simulations, and differential scanning fluorimetry assays and describe for the first time a structural model for human galectin-4. Our results provide insight into the structural role of the linker-peptide and shed light on the dynamic characteristics of the mechanism of carbohydrate recognition among tandem-repeat galectins.
Highlights
Galectins are proteins involved in diverse cellular contexts due to their capacity to decipher and respond to the information encoded by β-galactoside sugars
Galectin-4 is composed of 323 amino acids residues, which can be divided into an N-terminal domain, linker-peptide and C-terminal domain[19] (Supplementary Fig. S1)
One of the most notable properties about galectins and their carbohydrate recognition domains (CRDs) is the meticulous way in which they discriminate among different glycans, resulting in a variable and complex biological response[27,28]
Summary
Galectins are proteins involved in diverse cellular contexts due to their capacity to decipher and respond to the information encoded by β-galactoside sugars. Galectin-4 is a tandem-repeat galectin characterized by two carbohydrate recognition domains connected by a linker-peptide. Despite their relevance to cell function and pathogenesis, structural characterization of full-length tandem-repeat galectins has remained elusive. Our results provide insight into the structural role of the linker-peptide and shed light on the dynamic characteristics of the mechanism of carbohydrate recognition among tandem-repeat galectins. Galectins are a family of glycan-binding proteins characterized by their affinity for β-galactosides and the presence of one or more structurally conserved carbohydrate recognition domains (CRDs)[1]. Studies with tandem-repeat galectins have shown that the linker’s role, likely mediating the intramolecular interactions of CRDs, is associated with potency in inducing a specific biological response[8,9,10,11,12,13]. In order to unravel the structural mechanisms that govern signalling modulation by tandem-repeat galectins, we chose human galectin-4 as our model of study
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