Most yeast SH3 domains bind peptide targets with high intrinsic specificity

Abstract

A need exists to develop bioinformatics for predicting differences in protein function, especially for members of a domain family who share a common fold, yet are found in a diverse array of proteins. Many domain families have been conserved over large evolutionary spans and representative genomic data during these periods are now available. This allows a simple method for grouping domain sequences to reveal common and unique/specific binding residues. As such, we hypothesize that sequence alignment analysis of the yeast SH3 domain family across ancestral species in the fungal kingdom can determine whether each member encodes specific information to bind unique peptide targets. With this approach, we identify important specific residues for a given domain as those that show little conservation within an alignment of yeast domain family members (paralogs) but are conserved in an alignment of its direct relatives (orthologs). We find most of the yeast SH3 domain family members have maintained unique amino acid conservation patterns that suggest they bind peptide targets with high intrinsic specificity through varying degrees of non-canonical recognition. For a minority of domains, we predict a less diverse binding surface, likely requiring additional factors to bind targets specifically. We observe that our predictions are consistent with high throughput binding data, which suggests our approach can probe intrinsic binding specificity in any other interaction domain family that is maintained during evolution.

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© 2018 Brown et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. cc-by

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Brown, T., Brown, N., & Stollar, E.J.. 2018. Most yeast SH3 domains bind peptide targets with high intrinsic specificity. PLoS ONE, 13(2). https://doi.org/10.1371/journal.pone.0193128

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