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Protein context shapes the specificity of SH3 domain-mediated interactions in vivo

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Dionne, Ugo, Bourgault, Émilie, Dube, Alexandre K, Bradley, David, Chartier, Francois J. M, Dandage, Rohan, Dibyachintan, Sohem, Després, Philippe, Gish, Gerald, Pham, Ngoc Thu Hang, Létourneau, Myriam, Lambert, Jean-Philippe, Doucet, Nicolas ORCID: https://orcid.org/0000-0002-1952-9380, Bisson, Nicolas et Landry, Christian R. (2021). Protein context shapes the specificity of SH3 domain-mediated interactions in vivo Nature Communications , vol. 12 , nº 1597. p. 1-15. DOI: 10.1038/s41467-021-21873-2.

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Résumé

Protein-protein interactions (PPIs) between modular binding domains and their target peptide motifs are thought to largely depend on the intrinsic binding specificities of the domains. The large family of SRC Homology 3 (SH3) domains contribute to cellular processes via their ability to support such PPIs. While the intrinsic binding specificities of SH3 domains have been studied in vitro, whether each domain is necessary and sufficient to define PPI specificity in vivo is largely unknown. Here, by combining deletion, mutation, swapping and shuffling of SH3 domains and measurements of their impact on protein interactions in yeast, we find that most SH3s do not dictate PPI specificity independently from their host protein in vivo. We show that the identity of the host protein and the position of the SH3 domains within their host are critical for PPI specificity, for cellular functions and for key biophysical processes such as phase separation. Our work demonstrates the importance of the interplay between a modular PPI domain such as SH3 and its host protein in establishing specificity to wire PPI networks. These findings will aid understanding how protein networks are rewired during evolution and in the context of mutation-driven diseases such as cancer. The SRC Homology 3 (SH3) domains mediate protein-protein interactions (PPIs). Here, the authors assess the SH3-mediated PPIs in yeast, and show that the identity of the protein itself and the position of the SH3 both affect the interaction specificity and thus the PPI-dependent cellular functions.

Type de document: Article
Mots-clés libres: -
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 22 juin 2022 19:28
Dernière modification: 22 juin 2022 19:28
URI: https://espace.inrs.ca/id/eprint/12329

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