title: Impact of human galectin-1 binding to saccharide ligands on dimer dissociation kinetics and structure.
abstract: Endogenous lectins can control critical biological responses, including cell communication, signaling, angiogenesis and immunity by decoding glycan-containing information on a variety of cellular receptors and the extracellular matrix. Galectin-1 (Gal-1), a prototype member of the galectin family, displays only one carbohydrate recognition domain and occurs in a subtle homodimerization equilibrium at physiologic concentrations. Such equilibrium critically governs the function of this lectin signaling by allowing tunable interactions with a preferential set of glycosylated receptors. Here, we used a combination of experimental and computational approaches to analyze the kinetics and mechanisms connecting Gal-1 ligand unbinding and dimer dissociation processes. Kinetic constants of both processes were found to differ by an order of magnitude. By means of steered molecular dynamics simulations, the ligand unbinding process was followed monitoring water occupancy changes. By determining the water sites in a carbohydrate binding place during the unbinding process, we found that rupture of ligand-protein interactions induces an increase in energy barrier while ligand unbinding process takes place, whereas the entry of water molecules to the binding groove and further occupation of their corresponding water sites contributes to lowering of the energy barrier. Moreover, our findings suggested local asymmetries between the two subunits in the dimer structure detected at a nanosecond timescale. Thus, integration of experimental and computational data allowed a more complete understanding of lectin ligand binding and dimerization processes, suggesting new insights into the relationship between Gal-1 structure and function and renewing the discussion on the biophysics and biochemistry of lectin-ligand lattices.
authors.affiliation: Departamento de Química Biológica e IQUIBICEN-CONICET, and.|Departamento de Química Inorgánica, Analítica y Química Física e INQUIMAE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad de Buenos Aires C1428EHA, Argentina.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Romero
authors.affiliation: Departamento de Bioquímica and Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay.
authors.forename: Madia
authors.initials: M
authors.lastname: Trujillo
authors.affiliation: Departamento de Química Inorgánica, Analítica y Química Física e INQUIMAE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad de Buenos Aires C1428EHA, Argentina.
authors.forename: Darío A
authors.initials: DA
authors.lastname: Estrin
authors.affiliation: Departamento de Química Biológica e IQUIBICEN-CONICET, and santiagodilella@gmail.com gabyrabi@gmail.com.|Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, CONICET, Ciudad de Buenos Aires C1428ADN, Argentina.
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Rabinovich
authors.affiliation: Departamento de Química Biológica e IQUIBICEN-CONICET, and santiagodilella@gmail.com gabyrabi@gmail.com.|Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, CONICET, Ciudad de Buenos Aires C1428ADN, Argentina.
authors.forename: Santiago
authors.initials: S
authors.lastname: Di Lella
mesh_terms: D001665:Binding Sites; D019281:Dimerization; D037483:Galectin 1 / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011134:Polysaccharides / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D013816:Thermodynamics
chemical_list: D037483:Galectin 1; C445499:LGALS1 protein, human; D008024:Ligands; D011134:Polysaccharides
keywords: carbohydrate-binding protein; dimer dissociation kinetics; galectin-1; lattices; ligand-binding kinetics