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bioRxiv · 10.1101/2020.03.14.992149

Protein domain-based structural interfaces help interpret biologically-relevant interactions in the human interaction network.

Kilambi, K. P.·Xu, Q.·Kuthethur Gururaj, G.·Li, K.·Artavanis-Tsakonas, S.·Dunbrack, R. L.·Lehmann, A.
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Abstract

A high-quality map of the human protein-protein interaction (PPI) network can help us better understand complex genotype-phenotype relationships. Each edge between two interacting proteins supported through an interface in a three-dimensional (3D) structure of a protein complex adds credibility to the biological relevance of the interaction. Such structure-supported interactions would augment an interaction map primarily built using high-throughput cell-based biophysical methods. Here, we integrate structural information with the human PPI network to build the structure-supported human interactome, a subnetwork of PPI between proteins that contain domains or regions known to form interfaces in the 3D structures of protein complexes. We expand the coverage of our structure-supported human interactome by using Pfam-based domain definitions, whereby we include homologous interactions if a human complex structure is unavailable. The structure-supported interactome predicts one-eighth of the total network PPI to interact through domain-domain interfaces. It identifies with higher resolution the interacting subunits in multi-protein complexes and enables us to characterize functional and disease-relevant neighborhoods in the network map with higher accuracy, allowing for structural insights into disease-associated genes and pathways. We expand the structural coverage beyond domain-domain interfaces by identifying the most common non-enzymatic peptide-binding domains with structural support. Adding these interactions between protein domains on one side and peptide regions on the other approximately doubles the number of structure-supported PPI. The human structure-supported interactome is a resource to prioritize investigations of smaller-scale context-specific experimental PPI neighborhoods of biological or clinical significance. Short abstractA high-quality map of the human protein-protein interaction (PPI) network can help us better understand genotype-phenotype relationships. Each edge between two interacting proteins supported through an interface in a three-dimensional structure of a protein complex adds credibility to the biological relevance of the interaction aiding experimental prioritization. Here, we integrate structural information with the human interactome to build the structure-supported human interactome, a subnetwork of PPI between proteins that contain domains or regions known to form interfaces in the structures of protein complexes. The structure-supported interactome predicts one-eighth of the total PPI to interact through domain-domain interfaces. It identifies with higher resolution the interacting subunits in multi-protein complexes and enables us to structurally characterize functional, disease-relevant network neighborhoods. We also expand the structural coverage by identifying PPI between non-enzymatic peptide-binding domains on one side and peptide regions on the other, thereby doubling the number of structure-supported PPI.

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Kilambi, K. P., Xu, Q., Kuthethur Gururaj, G., Li, K., Artavanis-Tsakonas, S., Dunbrack, R. L., Lehmann, A.. 2020-03-16. Protein domain-based structural interfaces help interpret biologically-relevant interactions in the human interaction network.. https://doi.org/10.1101/2020.03.14.992149

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