Modelling human protein interaction networks as metric spaces has potential in disease research and drug target discovery

BMC Systems Biology

Junaid Gamieldien¹  Eric C Mwambene²  Emad Fadhal¹ 

[1] South African National Bioinformatics Institute/ MRC Unit for Bioinformatics Capacity Development, University of the Western Cape, Bellville 7530, South Africa;Department of Mathematics and Applied Mathematics, University of the Western Cape, Bellville 7530, South Africa

关键词: Disease genes;    Essential proteins;    Topological centrality;    Core-periphery structure;    Metric spaces;    Drug discovery;    Protein interaction networks;   

Others  :  864953
DOI  :  10.1186/1752-0509-8-68

 received in 2014-02-07, accepted in 2014-06-04,  发布年份 2014

【 摘 要 】

Background

We have recently shown by formally modelling human protein interaction networks (PINs) as metric spaces and classified proteins into zones based on their distance from the topological centre that hub proteins are primarily centrally located. We also showed that zones closest to the network centre are enriched for critically important proteins and are also functionally very specialised for specific ‘house keeping’ functions. We proposed that proteins closest to the network centre may present good therapeutic targets. Here, we present multiple pieces of novel functional evidence that provides strong support for this hypothesis.

Results

We found that the human PINs has a highly connected signalling core, with the majority of proteins involved in signalling located in the two zones closest to the topological centre. The majority of essential, disease related, tumour suppressor, oncogenic and approved drug target proteins were found to be centrally located. Similarly, the majority of proteins consistently expressed in 13 types of cancer are also predominantly located in zones closest to the centre. Proteins from zones 1 and 2 were also found to comprise the majority of proteins in key KEGG pathways such as MAPK-signalling, the cell cycle, apoptosis and also pathways in cancer, with very similar patterns seen in pathways that lead to cancers such as melanoma and glioma, and non-neoplastic diseases such as measles, inflammatory bowel disease and Alzheimer’s disease.

Conclusions

Based on the diversity of evidence uncovered, we propose that when considered holistically, proteins located centrally in the human PINs that also have similar functions to existing drug targets are good candidate targets for novel therapeutics. Similarly, since disease pathways are dominated by centrally located proteins, candidates shortlisted in genome scale disease studies can be further prioritized and contextualised based on whether they occupy central positions in the human PINs.

【 授权许可】

   
2014 Fadhal et al.; licensee BioMed Central Ltd.

【 图 表 】

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