Impact of human galectin-1 binding to saccharide ligands on dimer dissociation kinetics and structure

ROMERO, JUAN MANUEL; TRUJILLO, MADIA; ESTRIN, DARÍO ARIEL; RABINOVICH, GABRIEL ADRIÁN; DI LELLA, SANTIAGO

GLYCOBIOLOGY

OXFORD UNIV PRESS INC

Lugar: Oxford; Año: 2016

0959-6658

p { margin-bottom: 0.08in; direction: ltr; color: rgb(0, 0, 0); }p.western { font-family: "Liberation Serif","Times New Roman",serif; font-size: 12pt; }p.cjk { font-family: "DejaVu Sans","Angsana New"; font-size: 12pt; }p.ctl { font-family: "DejaVu Sans","Angsana New"; font-size: 12pt; }a.ctl:link { }Endogenous lectins can control criticalbiological responses, including cell communication, signaling,angiogenesis and immunity by decoding glycan-containing informationon a variety of cellular receptors and the extracellular matrix.Galectin-1 (Gal-1), a proto-type member of the galectin family,displays only one carbohydrate recognition domain (CRD) and occurs in a subtle homodimerization equilibrium at physiologic concentrations.Such equilibrium critically governs the function of this lectinsignaling by allowing tunable interactions with a preferential set ofglycosylated receptors. Here, we used a combination of experimentaland computational approaches to analyze the kinetics and mechanismsconnecting Gal-1-ligand unbinding and dimer dissociation processes.Kinetic constants of both processes were found to differ in an orderof magnitude. By means of steeredmolecular dynamics simulation, the ligand unbinding process wasfollowed, in combination with water occupancy changes. By determiningthe water sites in a carbohydrate binding place during the unbindingprocess, we found that rupture of ligand-protein interactions inducesan increase in energy barrier while ligand unbinding process takesplace, whereas the entry of water molecules to the binding groove andfurther occupation of their corresponding water sites contributes tolowering of the energy barrier. Moreover, our findings suggestedlocal asymmetries between the two subunits in the dimer structuredetected at a nanosecond timescale.Thus, integration of experimental andcomputational data allowed a more complete understanding oflectin-ligand binding and dimerization processes, suggesting newinsights into the relationship between Gal-1 structure and functionand renewing the discussion on the biophysics and biochemistry oflectin-ligand lattices.