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Discovery of protein interaction networks shared by diseases.

ABSTRACT: The study of protein-protein interactions is essential to define the molecular networks that contribute to maintain homeostasis of an organism's body functions. Disruptions in protein interaction networks have been shown to result in diseases in both humans and animals. Monogenic diseases disrupting biochemical pathways such as hereditary coagulopathies (e.g. hemophilia), provided a deep insight in the biochemical pathways of acquired coagulopathies of complex diseases. Indeed, a variety of complex liver diseases can lead to decreased synthesis of the same set of coagulation factors as in hemophilia. Similarly, more complex diseases such as different cancers have been shown to result from malfunctions of common proteins pathways. In order to discover, in high throughput, the molecular underpinnings of poorly characterized diseases, we present a statistical method to identify shared protein interaction network(s) between diseases. Integrating (i) a protein interaction network with (ii) disease to protein relationships derived from mining Gene Ontology annotations and the biomedical literature with natural language understanding (PhenoGO), we identified protein-protein interactions that were associated with pairs of diseases and calculated the statistical significance of the occurrence of interactions in the protein interaction knowledgebase. Significant correlations between diseases and shared protein networks were identified and evaluated in this study, demonstrating the high precision of the approach and correct non-trivial predictions, signifying the potential for discovery. In conclusion, we demonstrate that the associations between diseases are directly correlated to their underlying protein-protein interaction networks, possibly providing insight into the underlying molecular mechanisms of phenotypes and biological processes disrupted in related diseases.

SUBMITTER: Sam L

PROVIDER: S-EPMC2886192 | biostudies-other | 2007

REPOSITORIES: biostudies-other

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Discovery of protein interaction networks shared by diseases.

Sam Lee L Liu Yang Y Li Jianrong J Friedman Carol C Lussier Yves A YA

Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing 20070101

The study of protein-protein interactions is essential to define the molecular networks that contribute to maintain homeostasis of an organism's body functions. Disruptions in protein interaction networks have been shown to result in diseases in both humans and animals. Monogenic diseases disrupting biochemical pathways such as hereditary coagulopathies (e.g. hemophilia), provided a deep insight in the biochemical pathways of acquired coagulopathies of complex diseases. Indeed, a variety of comp ...[more]

PMID: 17992746

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Project description:BACKGROUND:Cohesin is a macromolecular complex that links sister chromatids together at the metaphase plate during mitosis. The links are formed during DNA replication and destroyed during the metaphase-to-anaphase transition. In budding yeast, the 14S cohesin complex comprises at least two classes of SMC (structural maintenance of chromosomes) proteins - Smc1 and Smc3 - and two SCC (sister-chromatid cohesion) proteins - Scc1 and Scc3. The exact function of these proteins is unknown. RESULTS:Searches of protein sequence databases have revealed new homologs of cohesin proteins. In mouse, Mmip1 (Mad member interacting protein 1) and Smc3 share 99% sequence identity and are products of the same gene. A phylogenetic tree of SMC homologs reveals five families: Smc1, Smc2, Smc3, Smc4 and an ancestral family that includes the sequences from the Archaea and Eubacteria. This ancestral family also includes sequences from eukaryotes. A cohesion interaction network, comprising 17 proteins, has been constructed using two proteomic databases. Genes encoding six proteins in the cohesion network share a common upstream region that includes the MluI cell-cycle box (MCB) element. Pairs of the proteins in this network share common sequence motifs that could represent common structural features such as binding sites. Scc2 shares a motif with Chk1 (kinase checkpoint protein), that comprises part of the serine/threonine protein kinase motif, including the active-site residue. CONCLUSIONS:We have combined genomic and proteomic data into a comprehensive network of information to reach a better understanding of the function of the cohesin complex. We have identified new SMC homologs, created a new SMC phylogeny and identified shared DNA and protein motifs. The potential for Scc2 to function as a kinase - a hypothesis that needs to be verified experimentally - could provide further evidence for the regulation of sister-chromatid cohesion by phosphorylation mechanisms, which are currently poorly understood.

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Discovery of protein interaction networks shared by diseases.

Publications

Discovery of protein interaction networks shared by diseases.

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