Bayesian Modeling of the Yeast SH3 Domain Interactome Predicts Spatiotemporal Dynamics of Endocytosis Proteins

Terrence Donnelly Center for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario, Canada.
PLoS Biology (Impact Factor: 9.34). 10/2009; 7(10):e1000218. DOI: 10.1371/journal.pbio.1000218
Source: PubMed


Author Summary
Significant diversity exists in protein structure and function, yet certain structural domains are used repeatedly across species to execute similar functions. The SH3 domain is one such common structural domain. It is found in signaling proteins and mediates protein–protein interactions by binding to short peptide sequences generally composed of proline. To investigate both the generality and selectivity of peptide binding by SH3 domains, we examined peptide specificity for almost all SH3 domains encoded within the proteome of the budding yeast, Saccharomyces cerevisiae, using a range of experimental methods. We found that although most of the intrinsic binding specificity for SH3 domains can be summarized by the two previously described canonical binding modes, each individual SH3 domain that we studied utilizes unique features of its cognate ligand to achieve binding selectivity. Moreover, some domains exhibit binding specificities that are distinct from the two canonical classes. We integrated peptide-SH3 domain binding data from three complementary screening techniques using a Bayesian statistical model to generate a protein–protein interaction network for the budding yeast SH3 domain family. This network was highly enriched in endocytosis proteins and their interactions. By examining these interactions in detail, we show that our SH3 domain network can be used to predict the temporal localization of several previously uncharacterized proteins to dynamic complexes that orchestrate the process of endocytosis.

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Available from: Gianni Cesareni
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    • "Three mutant forms of Abp1 (N*, C* and both N*C*) were kindly shared by D. Drubin (U.C. Berkeley) for this analysis [31]. In addition Abp1 has a C-terminal SH3 domain demonstrated to bind Ark1, Prk1, Scp1 and Srv2/CAP at endocytic sites [32], [33]. An Abp1 truncation lacking the SH3 domain was also generated. "
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    • "Consistent with this, we find that deletion of AIM44 affects the phosphorylation and localization of Hof1p, a protein that localizes to the bud neck, binds to septins and Myo1p, regulates contractile ring closure, and is detected as an Aim44p binding partner in a genome-wide protein interaction screen (Tonikian et al., 2009). We find that cell cycle–regulated changes in Hof1p abundance and phosphorylation are altered in aim44∆ cells. "
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    • "Since these domains usually have many interaction partners, a change in specificity would have very drastic effects by simultaneous disrupting tens to hundreds of interactions. Therefore, specificity changes are expected to be largely driven by divergence after duplication, as it has been observed for SH3 and PDZ domains (Tonikian et al, 2008, 2009; Xin et al, 2013). It is important to note that recognition might be also determined independently from the substrate recognition site by additional factors such as localization, expression or interaction with adaptor proteins. "
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