Phosphorylation of Tyrosine 841 Strongly Affects JAK3 Kinase’s Activation

Access full-text files




Sun, Shengjie
Li, Lin

Journal Title

Journal ISSN

Volume Title



Janus Kinase 3 (JAK3) plays a key role in the proliferation, development, and differentiation of various cells. It regulates gene expression by phosphorylation of Signal Transducer and Activators of Transcriptions (STATs). A new JAK3 kinase domain phosphorylation site was found, tyrosine-841 (Y841). The effects of phosphorylated tyrosine-841 (pY841) on ATP/ADP binding affinities of the JAK3 kinase domain were systematically studied and reported here. With the support of TACC, we applied long all-atom molecular dynamic simulations to study the effects of phosphorylation on Y841. The results show that pY841 reduces the size of the cleft between the N-lobe and C-lobe of the JAK3 kinase domain. However, when an ATP/ADP is bound to the kinase pY841 was found to enlarge the cleft. Additionally, for unphosphorylated JAK3 (JAK3-Y841), the binding forces between the kinase domain and ATP or ADP are similar. After phosphorylation of Y841, JAK3-pY841 exhibits more salt bridges and hydrogen bonds between ATP and kinase than ADP and kinase. Consequently, the electrostatic binding force between ATP and kinase is higher than that between ADP and kinase. The result is that compared to ADP, ATP is more attractive to JAK3 when Y841 is phosphorylated. Therefore, JAK3-pY841 tends to bind ATP rather than ADP.



LCSH Subject Headings