Kazemein Jasemi, N.S.; Mehrabipour, M.; Magdalena Estirado, E.; Brunsveld, L.; Dvorsky, R.; Ahmadian, M.R. Functional Classification and Interaction Selectivity Landscape of the Human SH3 Domain Superfamily. Cells2024, 13, 195.
Kazemein Jasemi, N.S.; Mehrabipour, M.; Magdalena Estirado, E.; Brunsveld, L.; Dvorsky, R.; Ahmadian, M.R. Functional Classification and Interaction Selectivity Landscape of the Human SH3 Domain Superfamily. Cells 2024, 13, 195.
Kazemein Jasemi, N.S.; Mehrabipour, M.; Magdalena Estirado, E.; Brunsveld, L.; Dvorsky, R.; Ahmadian, M.R. Functional Classification and Interaction Selectivity Landscape of the Human SH3 Domain Superfamily. Cells2024, 13, 195.
Kazemein Jasemi, N.S.; Mehrabipour, M.; Magdalena Estirado, E.; Brunsveld, L.; Dvorsky, R.; Ahmadian, M.R. Functional Classification and Interaction Selectivity Landscape of the Human SH3 Domain Superfamily. Cells 2024, 13, 195.
Abstract
SRC homology 3 (SH3) domains are critical interaction modules that orchestrate the assembly of protein complexes involved in diverse biological processes. They facilitate transient protein-protein interactions by selectively interacting with proline-rich motifs (PRMs). A database search revealed 298 SH3 domains in 221 human proteins. Multiple sequence alignment of human SH3 domains is useful for phylogenetic analysis and determination of their selectivity towards PRM-containing peptides (PRPs). However, a more precise functional classification of SH3 domains is achieved by constructing a phylogenetic tree only from PRM-binding residues and using existing SH3-PRP structures and biochemical data to determine the specificity within each of the 10 families for particular PRPs. In addition, the C-terminal proline-rich domain of the RAS activator SOS1 covers 13 of the 14 recognized proline-rich consensus sequence motifs, encompassing differential PRP pattern selectivity among all SH3 families. To evaluate binding capabilities and affinities, we conducted fluorescence dot blot and polarization experiments using 25 representative SH3 domains and various PRPs derived from SOS1. Our analysis has identified 45 interacting pairs with binding affinities ranging from 0.2 to 125 micromolar out of 300 tested and potential new interactors of SOS1. Furthermore, it establishes a framework to bridge the gap between SH3 and PRP interactions and provides predictive insights into potential interactions of SH3 domains with PRMs based on sequence specifications. This novel framework has the potential to enhance the understanding of protein networks mediated by SH3-PRM interactions and be utilized as a general approach for other domain-peptide interactions.
Biology and Life Sciences, Biochemistry and Molecular Biology
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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