Effects of the I682F mutation on JAK2's activity, structure and stability.

Janus kinase 2 (JAK2) plays important roles in the regulation of varieties cellular processes including cell migration, proliferation and apoptosis. JAK2 I682F genetic mutation existed in the 4-8% of B-cell acute lymphoblastic leukemia (B-ALL). However, roles of this mutation in the development of B-ALL are still unknown. In order to investigation the mechanism of the JAK2 I682F mutation led to B-ALL, series of mutations were constructed. Mutations I682F, I682G, I682D and I682S significantly increased JAK2's activity and decreased its structural stability, while the I682L mutation almost had no effect on JAK2's activity and structural stability. Furthermore, the spectroscopic experiments implied that mutations I682F, I682G, I682D and I682S impaired the structure of JAK2 JH2 domain, and led JAK2 to the partially unfolded state. It may be this partially unfolded state that caused JAK2 I682F constitutive activation. This study provides clues in understanding the mechanism of the JAK2 I682F mutation caused B-ALL.