Abstract
BackgroundWe 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.ResultsWe 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.ConclusionsBased 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.
Highlights
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
By using a more precise approach that formally models PINs as metric spaces and classifies proteins into zones based on their distance from the topological centre, that hub proteins are not distributed randomly and are the main feature of zones closest to the network centre
Human PINs have a core-periphery structure when modelled as metric spaces We modelled the human functional protein interaction network (HFPIN) [33], which consists of 9448 nodes and 181706 interactions and the highly curated and currently largest available human signalling network (HSN) [34,35], which consists of 6291 nodes and 62737 interactions
Summary
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. Nodes of PINs have been ranked by metrics such as degree, betweenness, eccentricity and closeness The latter, which is defined as the reciprocal of the average geodetic distance between a given node and others, has featured [25]. Using these metrics, a classification of proteins into core and periphery classes has been defined as a way to predict a protein’s relative importance in the network
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
