Deep mutational scanning reveals pharmacologically relevant insights into TYK2 signaling and disease
Howard, C. J.; Abell, N. S.; Warneford-Thomson, R. R.; Mahdavi, E.; Su, A. L.; Resnick, C.; Mohammed, N.; Thompson, E. M.; Holzinger, E. R.; Catalano, K.; Hukku, A.; Mintier, G. A.; MacKenzie, M.; Jiang, B. L.; Barbosa Rabago, D.; Chan, A.; Ntimi, C.; Weiler, K. N.; Wilson, S. C.; Maranville, J. C.; Sheth, P. R.; Plenge, R. M.; Kosuri, S.; Dickel, D. E.
Show abstract
Tyrosine Kinase 2 (TYK2) is a genetically defined target for autoimmune disease, with first-generation inhibitors showing clinical success in some but not all associated indications. A deeper understanding of TYK2 structure-function, protein-ligand interactions, and the impact of human variants could inform next-generation therapeutics. Here, we applied Deep Mutational Scanning (DMS) to assess >23,000 amino acid substitutions across two TYK2 functions: IFN- signaling and protein abundance. This enabled high-resolution structure-function mapping and the identification of novel allosteric sites. By coupling DMS with inhibitor treatment, we uncovered variants that modulate compound potency. We also show that human variants - both common and rare - that are protective against autoimmune phenotypes reduce TYK2 protein abundance. Together, these findings demonstrate that DMS can prospectively reveal novel druggable sites, clarify structure-activity relationships (SAR), and highlight TYK2 degradation as a potential therapeutic strategy in autoimmunity.
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