Known allosteric proteins have central roles in genetic disease

TL;DR

This study demonstrates that allosteric proteins are central to genetic disease networks, contributing significantly to various diseases and being enriched with disease-associated variants, highlighting their importance in disease mechanisms.

Contribution

It provides the first comprehensive quantification of the role of allosteric proteins in genetic diseases and their network centrality, emphasizing their potential as therapeutic targets.

Findings

Allosteric proteins are central in disease networks across major disease types.

Variants near allosteric proteins are enriched in cancer GWAS data.

Their disease importance is linked to network centrality, not dynamical properties.

Abstract

Allostery is a form of protein regulation, where ligands that bind sites located apart from the active site can modify the activity of the protein. The molecular mechanisms of allostery have been extensively studied, because allosteric sites are less conserved than active sites, and drugs targeting them are more specific than drugs binding the active sites. Here we quantify the importance of allostery in genetic disease. We show that 1) known allosteric proteins are central in disease networks, and contribute to genetic disease and comorbidities much more than non-allosteric proteins, in many major disease types like hematopoietic diseases, cardiovascular diseases, cancers, diabetes, or diseases of the central nervous system. 2) variants from cancer genome-wide association studies are enriched near allosteric proteins, indicating their importance to polygenic traits; and 3) the importance of allosteric proteins in disease is due, at least partly, to their central positions in protein-protein interaction networks, and probably not due to their dynamical properties.