Controllability analysis of the directed human protein interaction network identifies disease genes and drug targets

TL;DR

This study analyzes the controllability of a large human protein interaction network to identify key proteins that are linked to diseases and can serve as potential drug targets, revealing new insights into disease mechanisms.

Contribution

It introduces a structural controllability framework for the human PPI network and identifies indispensable proteins as novel disease genes and drug targets.

Findings

21% of proteins are indispensable in the network

Indispensable proteins are primary targets of mutations, viruses, and drugs

56 cancer-associated genes are indispensable, with 46 being novel discoveries

Abstract

The protein-protein interaction (PPI) network is crucial for cellular information processing and decision-making. With suitable inputs, PPI networks drive the cells to diverse functional outcomes such as cell proliferation or cell death. Here we characterize the structural controllability of a large directed human PPI network comprised of 6,339 proteins and 34,813 interactions. This allows us to classify proteins as "indispensable", "neutral" or "dispensable", which correlates to increasing, no effect, or decreasing the number of driver nodes in the network upon removal of that protein. We find that 21% of the proteins in the PPI network are indispensable. Interestingly, these indispensable proteins are the primary targets of disease-causing mutations, human viruses, and drugs, suggesting that altering a network's control property is critical for the transition between healthy and disease states. Furthermore, analyzing copy number alterations data from 1,547 cancer patients reveals that 56 genes that are frequently amplified or deleted in nine different cancers are indispensable. Among the 56 genes, 46 of them have not been previously associated with cancer. This suggests that controllability analysis is very useful in identifying novel disease genes and potential drug targets.