Known allosteric proteins have central roles in genetic disease.
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, contribute to genetic disease and comorbidities much more than non-allosteric proteins, and there is an association between being allosteric and involvement in disease; 2) they are enriched in many major disease types like hematopoietic diseases, cardiovascular diseases, cancers, diabetes, or diseases of the central nervous system; 3) variants from cancer genome-wide association studies are enriched near allosteric proteins, indicating their importance to polygenic traits; and 4) the importance of allosteric proteins in disease is due, at least partly, to their central positions in protein-protein interaction networks, and less due to their dynamical properties.
Acknowledgements: We thank Sergio Ruiz-Carmona and Loïc Lannelongue for critical reading of the manuscript.
Funder: Cambridge-Baker Systems Genomics Initiative
Funder: Munz Chair of Cardiovascular Prediction and Prevention
Funder: Health Data Research UK
Funder: Victorian Government’s Operational Infrastructure Support Program
British Heart Foundation (RG/18/13/33946)
National Institute for Health and Care Research (IS-BRC-1215-20014)
British Heart Foundation (None)