Dissection of hubs and bottlenecks in a protein-protein interaction network.

Analysis of degree centrality in conjunction with betweenness centrality of proteins in a human protein-protein interaction network revealed three categories of centrally important proteins: a) proteins with high degree and betweenness (hub-bottlenecks denoted as MX), b) proteins with high betweenness and low degree (non-hub-bottlenecks/pure bottlenecks denoted as PB) and c) proteins with high degree and low betweenness (hub-non-bottlenecks/pure hubs denoted as PH). When subjected to a detailed statistical analysis of their molecular-level properties, the proteins belonging to each of these categories were found to be associated with distinct canonical molecular properties, i.e., "molecular markers". The MX proteins are a) conformationally versatile, mainly comprising of essential proteins, b) the targets for interactions by the proteins of viral and bacterial pathogens, c) evolutionally constrained, involved in multiple pathways, enriched with disease genes and d) involved in the functions such as protein stabilization, phosphorylation, and mRNA slicing processes. PB proteins are a) enriched with extracellular and cancer-related proteins, b) enriched with the approved drug targets and c) involved in cell-cell signaling processes. Finally, PH are a) structurally versatile, b) enriched with essential proteins primarily involved in housekeeping processes (transcription and replication). The fact that the proteins belonging to these three categories form three distinct sets in terms of their molecular properties reveals the existence of trichotomy among hubs and bottlenecks, and this knowledge is of paramount importance while prioritizing protein targets for further studies such as drug design and disease association studies based on their network centrality values.