Perturbing dimer interactions and allosteric communication modulates the immunosuppressive activity of human galectin-7

The design of allosteric modulators to control protein function is a key objective in drug discovery programs. Altering functionally essential allosteric residue networks provides unique protein family subtype specificity, minimizes unwanted off-target effects, and helps avert resistance acquisition...

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Published in:The Journal of biological chemistry 2021-11, Vol.297 (5), p.101308-101308, Article 101308
Main Authors: Pham, N. T. Hang, Létourneau, Myriam, Fortier, Marlène, Bégin, Gabriel, Al-Abdul-Wahid, M. Sameer, Pucci, Fabrizio, Folch, Benjamin, Rooman, Marianne, Chatenet, David, St-Pierre, Yves, Lagüe, Patrick, Calmettes, Charles, Doucet, Nicolas
Format: Article
Language:English
Subjects:
Allosteric Regulation
allostery
apoptosis
Apoptosis - genetics
Apoptosis - immunology
cancer
galectins
Galectins - chemistry
Galectins - genetics
Galectins - immunology
glycobiology
Humans
Immune Tolerance
Jurkat Cells
protein dynamics
Protein Multimerization - genetics
Protein Multimerization - immunology
T-Lymphocytes - immunology
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Summary:The design of allosteric modulators to control protein function is a key objective in drug discovery programs. Altering functionally essential allosteric residue networks provides unique protein family subtype specificity, minimizes unwanted off-target effects, and helps avert resistance acquisition typically plaguing drugs that target orthosteric sites. In this work, we used protein engineering and dimer interface mutations to positively and negatively modulate the immunosuppressive activity of the proapoptotic human galectin-7 (GAL-7). Using the PoPMuSiC and BeAtMuSiC algorithms, mutational sites and residue identity were computationally probed and predicted to either alter or stabilize the GAL-7 dimer interface. By designing a covalent disulfide bridge between protomers to control homodimer strength and stability, we demonstrate the importance of dimer interface perturbations on the allosteric network bridging the two opposite glycan-binding sites on GAL-7, resulting in control of induced apoptosis in Jurkat T cells. Molecular investigation of G16X GAL-7 variants using X-ray crystallography, biophysical, and computational characterization illuminates residues involved in dimer stability and allosteric communication, along with discrete long-range dynamic behaviors involving loops 1, 3, and 5. We show that perturbing the protein–protein interface between GAL-7 protomers can modulate its biological function, even when the overall structure and ligand-binding affinity remains unaltered. This study highlights new avenues for the design of galectin-specific modulators influencing both glycan-dependent and glycan-independent interactions.
ISSN:0021-9258
1083-351X
DOI:10.1016/j.jbc.2021.101308