Probing Protein Interaction Networks by Combining MS-Based Proteomics and Structural Data Integration

Abstract

Protein-protein interactions play a major role in the molecular machinery of life and various techniques such as AP-MS are dedicated to their identification. However, those techniques return lists of proteins devoid of organizational structure, not detailing which proteins interact with which others. Proposing a hierarchical view of the interactions between the members of the flat list becomes highly tedious for large datasets when done by hand. To help hierarchize this data, we introduce a new bioinformatics protocol that integrates information of the multimeric protein 3D structures available in the Protein Data Bank using remote homology detection, as well as information related to Short Linear Motifs and interaction data from the BioGrid. We illustrate on two unrelated use-cases of different complexity how our approach can be useful to decipher the network of interactions hidden in the list of input proteins, and how it provides added value compared to state-of-the-art resources such as Interactome3D or STRING. Particularly, we show the added value of using homology detection to distinguish between orthologs and paralogs, and to distinguish between core obligate and more facultative interactions. We also demonstrate the potential of considering interactions occurring through Short Linear Motifs.

Proteo3Dnet: a web server for the integration of structural information with interactomics data

“…Advantages of our protocol over the other approaches have been recently discussed through two case studies from published AP-MS data ( 16 ). Here we introduce two new case studies showing how Proteo3Dnet can assist users to analyse their data.…”

“…Recently, we have proposed Proteo3Dnet ( 16 ), a new integrative pipeline which stands out from the state of the art mainly by its detection of distant homologies and combination of domain-domain interactions as well as motif-domain contacts. We have shown that our method can identify some direct interaction partners to which proteomics techniques and other algorithms are blind.…”

SLiMAn: An Integrative Web Server for Exploring Short Linear Motif-Mediated Interactions in Interactomes

“…Combining proteomics data with 3D searches and comparative modeling has now emerged as a valuable tool to compensate the limitations of most of the above approaches. Servers such as Interactome3D and Proteo3Dnet , allow one to dig efficiently into available 3D structures, gathered in the Protein Data Bank (PDB) to unravel likely physical interactions within a set of proteins. The Complex Portal () is also often used to match the proteins involved in 297 already known mammalian complexes at the structural level.…”

SLiMAn: an integrative web server for exploring short linear motif-mediated interactions in interactomes

“…Combining proteomics data with 3D search and comparative modeling has now emerged as a valuable tool to compensate limitations of each of the above approaches. Servers such as Interactome3D 9 and Proteo3Dnet 10,11 allow one to dig efficiently into available 3D structures, gathered in the Protein Data Bank (PDB 12 ) to unravel likely physical interactions within a set of proteins. The Complex Portal (www.ebi.ac.uk/complexportal/) is also often used to match the proteins involved in 297 already known mammalian complexes at the structural level.…”