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Allosteric network analysis in galectin-7 uncovers key residues controlling positive cooperativity between two opposite glycan binding sites

Pham, Ngoc Thu Hang; Paré, Alex; Létourneau, Myriam; Fortier, Marlène; Begin, Gabriel; Chatenet, David ORCID logoORCID: https://orcid.org/0000-0002-7270-4328; St-Pierre, Yves ORCID logoORCID: https://orcid.org/0000-0002-1948-2041; Lague, Patrick; Calmettes, Charles ORCID logoORCID: https://orcid.org/0000-0002-2542-4382 et Doucet, Nicolas ORCID logoORCID: https://orcid.org/0000-0002-1952-9380 (2022). Allosteric network analysis in galectin-7 uncovers key residues controlling positive cooperativity between two opposite glycan binding sites In: 36th Annual Symposium of the Protein-Society, July 07-10, 2022, San Francisco, CA.

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Human galectin-7 (GAL-7) plays dual roles as a pro- and anti-tumorigenic protein. It is a prototypical galectin characterized by a beta-galactoside binding site (GBS) and a homodimeric molecular architecture. Due to high GBS similarity among several galectin homologs in the cell, the development of GAL-7 glycan-based inhibitors aimed at perturbing glycoreceptor interactions remains a high-risk strategy plagued by unwanted off-target effects. Functional allosteric modulation thus represents an alternative strategy to improve GAL-7 selectivity. In the present work, we used network analysis to predict residue positions that allosterically modulate the pro-apoptotic activity mediated by GAL-7. We uncovered how crucial residue contacts at the dimer interface can be altered to control its biological function by allosterically modulating communication between protomers. We show that introducing a covalent disulfide bridge at position G16 strengthens protomer interactions to improve positive cooperativity by favoring interprotomer communication between residue pair Arg20-Asp103 at the dimer interface. Accordingly, we describe a new approach to investigate the global communication flow between the two GBSs, revealing that altered electrostatic interactions between residue pairs Arg20-Asp103 and Arg22-Asp103 reduces interprotomer communication. This is consistent with decreased pro-apoptotic activity in GAL-7 variants R20A, R22A, and D103A, further suggesting that Arg20, Arg22, and Asp103 are potentially controlling positive cooperativity in GAL-7. Our study illustrates how the shortest pathway analysis can illuminate global flow communication to reveal key residues controlling allosteric communication between long-range functional sites within a protein.

Type de document: Document issu d'une conférence ou d'un atelier
Informations complémentaires: Présentation orale ABS029 Protein Science (2023) 32 (suppl 1) https://doi.org/10.1002/pro.4494 Award Winners/Abstracts from the 36th Annual Symposium of The Protein Society, July 7 – 10, 2022
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Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 04 janv. 2024 07:50
Dernière modification: 04 janv. 2024 07:50
URI: https://espace.inrs.ca/id/eprint/13452

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