Engineering selective competitors for the discrimination of highly conserved protein-protein interaction modules

Charlotte Rimbault, Kashyap Maruthi, Christelle Breillat, Camille Genuer, Sara Crespillo, Virginia Puente-Muñoz, Ingrid Chamma, Isabel Gauthereau, Ségolène Antoine, Coraline Thibaut, Fabienne Wong Jun Tai, Benjamin Dartigues, Dolors Grillo-Bosch, Stéphane Claverol, Christel Poujol, Daniel Choquet, Cameron D. Mackereth () and Matthieu Sainlos ()
Additional contact information
Charlotte Rimbault: Centre National de la Recherche Scientifique
Kashyap Maruthi: Institut Européen de Chimie et Biologie, Univ. Bordeaux
Christelle Breillat: Centre National de la Recherche Scientifique
Camille Genuer: Centre National de la Recherche Scientifique
Sara Crespillo: Centre National de la Recherche Scientifique
Virginia Puente-Muñoz: Centre National de la Recherche Scientifique
Ingrid Chamma: Centre National de la Recherche Scientifique
Isabel Gauthereau: Centre National de la Recherche Scientifique
Ségolène Antoine: Centre National de la Recherche Scientifique
Coraline Thibaut: Centre National de la Recherche Scientifique
Fabienne Wong Jun Tai: University of Bordeaux, CBiB-LaBRI
Benjamin Dartigues: University of Bordeaux, CBiB-LaBRI
Dolors Grillo-Bosch: Centre National de la Recherche Scientifique
Stéphane Claverol: University of Bordeaux
Christel Poujol: University of Bordeaux, US 4 INSERM
Daniel Choquet: Centre National de la Recherche Scientifique
Cameron D. Mackereth: Institut Européen de Chimie et Biologie, Univ. Bordeaux
Matthieu Sainlos: Centre National de la Recherche Scientifique

Nature Communications, 2019, vol. 10, issue 1, 1-20

Abstract: Abstract Designing highly specific modulators of protein-protein interactions (PPIs) is especially challenging in the context of multiple paralogs and conserved interaction surfaces. In this case, direct generation of selective and competitive inhibitors is hindered by high similarity within the evolutionary-related protein interfaces. We report here a strategy that uses a semi-rational approach to separate the modulator design into two functional parts. We first achieve specificity toward a region outside of the interface by using phage display selection coupled with molecular and cellular validation. Highly selective competition is then generated by appending the more degenerate interaction peptide to contact the target interface. We apply this approach to specifically bind a single PDZ domain within the postsynaptic protein PSD-95 over highly similar PDZ domains in PSD-93, SAP-97 and SAP-102. Our work provides a paralog-selective and domain specific inhibitor of PSD-95, and describes a method to efficiently target other conserved PPI modules.

Date: 2019
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DOI: 10.1038/s41467-019-12528-4

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