Insights on the alteration of functionality of a tyrosine kinase 2 variant: a molecular dynamics study

The tyrosine kinase 2 protein (Tyk2), encoded by the TYK2 gene, has a crucial role in signal transduction and the pathogenesis of many diseases. A single nucleotide polymorphism of the TYK2 gene, SNP rs34536443, is of major importance, since it has been shown to confer protection against various, mainly, autoimmune diseases. This polymorphism results in a Pro to Ala change at amino acid position 1104 of the encoded Tyk2 protein that affects its enzymatic activity. However, the details of the underlined mechanism are unknown. To address this issue, in this study, we used molecular dynamics simulations on the kinase domains of both wild type and variant Tyk2 protein.

Our MD results provided information, at atomic level, on the consequences of the Pro1104 to Ala substitution on the structure and dynamics of the kinase domain of Tyk2 and suggested reduced enzymatic activity of the resulting protein variant due to stabilization of inactive conformations, thus adding to knowledge towards the elucidation of the protection mechanism against autoimmune diseases associated with this point mutation.