Tyrosine kinase 2 (TYK2) (TYK2)

Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family of non-receptor tyrosine kinases that plays a central role in the signaling pathways of several pro-inflammatory cytokines, including interleukin-12 (IL-12), interleukin-23 (IL-23), and type I interferons [1, 11, 16]. The TYK2 protein contains a catalytic kinase domain (JH1) and a regulatory pseudokinase domain (JH2) [11]. While the JH2 domain lacks significant enzymatic activity, it serves as a critical allosteric regulator that maintains the JH1 domain in an autoinhibited state [1, 9, 15]. In autoimmune and inflammatory diseases such as psoriasis, psoriatic arthritis, and systemic lupus erythematosus, overactive TYK2 signaling drives pathogenic immune responses [2, 3, 6, 16]. Modern therapeutic agents, such as deucravacitinib, specifically target the TYK2 pseudokinase domain rather than the highly conserved ATP-binding site of the catalytic domain [4, 10, 15]. This allosteric mechanism stabilizes the inactive conformation of the enzyme, providing exceptional selectivity for TYK2 over other JAK family members (JAK1, JAK2, and JAK3) and thereby reducing the risk of off-target side effects like myelosuppression and thromboembolism [2, 4, 16].

Other names

JH2 domainJanus homology 2 domainTyrosine kinase 2 regulatory domainTYK2 pseudokinase domain

Allosteric inhibition by binding to the pseudokinase (JH2) domain, which stabilizes the autoinhibitory interaction with the catalytic (JH1) domain and locks the enzyme in an inactive conformation [1, 3, 4, 9, 15].