Disease network.

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.

别构效应（allostery）是蛋白质调控的一种重要形式，指结合于远离活性位点（active site）的配体（ligand）可改变蛋白质的活性。由于别构位点（allosteric sites）相较于活性位点保守性更低，靶向别构位点的药物相较于结合活性位点的药物特异性更强，因此别构效应的分子机制已得到广泛研究。本研究量化了别构效应在遗传疾病中的重要性，研究结果显示：1）已知的别构蛋白质在疾病网络中处于核心地位，相较于非别构蛋白质，其对遗传疾病及共病（comorbidities）的贡献更为显著，且别构特性与疾病关联存在相关性；2）别构蛋白质在多种重大疾病类型中显著富集，例如造血系统疾病、心血管疾病、癌症、糖尿病以及中枢神经系统疾病；3）癌症全基因组关联研究（cancer genome-wide association studies）中的变异位点在别构蛋白质附近富集，表明别构蛋白质对多基因性状具有重要意义；4）别构蛋白质在疾病中的重要性至少部分源于其在蛋白质-蛋白质相互作用网络（protein-protein interaction networks）中的核心位置，而与其动态特性的关联度相对较低。