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Insights into the Homodimeric Interface of Human Galectin-7: From Structural and BiophysicalCharacterization to Immunosuppressive Activity Assays

Pham, Ngoc Thu Hang; Létourneau, Myriam; Pinoteau, Marie-Aude; Fortier, Marlène; Gagnon, Jacinthe; Egesborg, Philippe; Chatenet, David; St-Pierre, Yves; Calmettes, Charles; Doucet, Nicolas . Insights into the Homodimeric Interface of Human Galectin-7: From Structural and BiophysicalCharacterization to Immunosuppressive Activity Assays In: 32nd Annual Symposium of The Protein Society, July 9-12 2018, Boston, Masachusetts.

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Résumé

Galectins are lectin proteins that specifically bind beta-galactoside sugars. These proteins are subdivided into3 groups, including the important prototypical galectin type characterized by a homodimeric molecular orga-nization of its carbohydrate recognition domain (CRD). The prototypical human galectin-7 (Gal-7) has been implicated in breast and ovarian cancer progression due to its immunosuppressive properties. Gal-7 can trig-ger T-cell apoptosis via a glycan binding site (GBS) that recognizes T-cell glycoreceptors. Previously, drugdevelopment favored GBS inhibition to limit Gal-7 binding to immune cells. However, this strategy was metwith limited success due to low GBS inhibitor specificity and high GBS similarity among different galectinhomologs in the cell. Since the immunosuppressive activity of Gal-7 appears to require a homodimeric form ofthe protein, perturbing dimer formation could alter its biological function and act as a novel strategy toincrease drug specificity and lower off-target binding. We have developed a structural protein-protein interac-tion strategy to dissect the molecular importance of the homodimeric architecture in Gal-7 function. In thisstudy, we present X-ray crystallography structures of Gal-7 mutants at the homodimeric interface, in absenceand presence of -galactoside. The thermal stability of these mutants and their binding affinity towards knownGal-7 ligands were evaluated using circular dichroism and isothermal titration calorimetry, respectively. Finally,the biological activity of these Gal-7 interface mutants was tested on Jurkat T-cells by monitoring their abilityto induce apoptosis. These results will be an asset in the design of new galectin inhibitors targeting the homo-dimeric interface of Gal-7.

Type de document: Document issu d'une conférence ou d'un atelier
Informations complémentaires: Protein Science (2018), 27 (s1), 63-64 ABS120
Mots-clés libres: -
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 20 nov. 2019 15:45
Dernière modification: 20 nov. 2019 15:45
URI: http://espace.inrs.ca/id/eprint/8162

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