genome-wide-protein-protein-interaction-screening-protein-fragment

Genome-wide Protein-protein Interaction Screening by Protein-fragment Complementation Assay (PCA) in Living Cells

Proteins are the building blocks, effectors and signal mediators of cellular processes. A protein&#8217;s function, regulation and localization often ...

Université Laval

Gene duplication plays a key role in the evolution of protein-protein interaction (PPI) networks. After a gene duplication event, paralogous proteins may diverge through the gain and loss of PPIs. This divergence can be explained by two non-exclusive mechanisms. First, mutations may accumulate in the coding sequences of the paralogs and affect their protein sequences, which can modify, for instance, their binding interfaces and thus their interaction specificity. Second, mutations may accumulate in the non-coding region of the genes and affect their regulatory sequences. The resulting changes in expression profiles can lead to paralogous proteins being differentially expressed and occurring in the cell with different sets of potential interaction partners. These changes could also alter splicing regulation and lead to the inclusion or exclusion of alternative exons. The evolutionary role of these regulatory mechanisms remains largely unexplored. We use bioinformatics analyses of existing PPI data and proteome-wide PPI screening to show that the divergence of transcriptional regulation between paralogs plays a significant role in determining their PPI specificity. Because many gene duplication events are followed by rapid changes in transcriptional regulation, our results suggest that PPI networks may be rewired by gene duplication, without the need for protein to diverge in their binding specificities. This article is part of a Special Issue entitled: From protein structures to clinical applications.

Transcriptional divergence plays a role in the rewiring of protein interaction networks after gene duplication.

Over the past decade, the study of protein interaction networks (PINs) has shed light on the organizing principles of living cells. However, PINs have been mostly mapped in one single condition. We outline three of the most promising avenues of investigation in this field, namely the study of first, how PINs are rewired by mutations and environmental perturbations; secondly, how inter-species interactions affect PIN achitectures; thirdly, what mechanisms and forces drive PIN evolution. These investigations will unravel the dynamics and condition dependence of PINs and will thus lead to a better functional annotation of network architecture. One major challenge to reach these goals is the integration of PINs with other cellular regulatory networks in the context of complex cellular phenotypes.

Integrative avenues for exploring the dynamics and evolution of protein interaction networks.

Cells deploy diverse mechanisms to physiologically adapt to potentially detrimental perturbations. These mechanisms include changes in the organization of protein-protein interaction networks (PINs). Most PINs characterized to date are portrayed in a single environmental condition and are thus likely to miss important connections among biological processes. In this report, we show that the yeast DHFR-PCA on high-density arrays allows to detects modulations of protein-protein interactions (PPIs) in different conditions by testing more than 1000 PPIs in standard and in a drug-inducing DNA damage conditions. We identify 156 PPIs that show significant modulation in response to DNA damage. We provide evidence that modulated PPIs involve essential genes (NOP7, EXO84 and LAS17) playing critical roles in response to DNA damage. Additionally, we show that a significant proportion of PPI changes are likely explained by changes in protein localization and, to a lesser extent, protein abundance. The protein interaction modules affected by changing PPIs support the role of mRNA stability and translation, protein degradation and ubiquitylation and the regulation of the actin cytoskeleton in response to DNA damage. Overall, we provide a valuable tool and dataset for the study of the rewiring of PINs in response to environmental perturbations.

Article	Year
Transcriptional divergence plays a role in the rewiring of protein interaction networks after gene duplication. Journal of proteomics\| PubMed ID: 23063722	2013
Integrative avenues for exploring the dynamics and evolution of protein interaction networks. Current opinion in biotechnology\| PubMed ID: 23571097	2013
Modulation of the yeast protein interactome in response to DNA damage. Journal of proteomics\| PubMed ID: 24262151	2014

Samuel Rochette

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