Mechanisms of constitutive activation of Janus kinase 2-V617F revealed at the atomic level through molecular dynamics simulations.
BACKGROUND
The tyrosine kinase Janus kinase 2 (JAK2) is important in triggering nuclear translocation and regulation of target genes expression through signal transducer and activator of transcription pathways. The valine-to-phenylalanine mutation at amino acid 617 (V617F), which results in the deregulation of JAK2, has been implicated in the oncogenesis of chronic myeloproliferative disease. However, both the mechanism of JAK2 autoinhibition and the mechanism of V617F constitutive activation remain unclear.


METHODS
In this work, the authors used molecular dynamics simulation techniques to establish plausible mechanisms of JAK2 autoinhibition and V617F constitutive activation at the atomic level.


RESULTS
In wild-type JAK2, the activation loop of JAK2-homology domain 1 (JH1) is pulled toward the JH1/JH2 interface through interactions with key residues of JH2, especially S591, F595, and V617, and stabilizes the inactivated form of JH1. In the case of V617F, through the aromatic ring-ring stacking interaction, F617 blocks the interaction of JH1 the activation loop, S591, and F595, thus causing the JH1 activation loop to move back to its activated form.


CONCLUSIONS
The current results indicated that this simulation-derived mechanism of JAK2 autoregulation is consistent with current available experimental evidence and may lead to a deeper understanding of JAK2 and other kinase systems that are regulated by pseudokinases.
Lee
Tai-Sung
TS
Department of Chemistry, University of Minnesota, Minneapolis, Minnesota, USA. leex2750@umn.edu
Ma
Wanlong
W
Zhang
Xi
X
Giles
Francis
F
Kantarjian
Hagop
H
Albitar
Maher
M
D004789:Enzyme Activation; D004795:Enzyme Stability; D053614:Janus Kinase 2 / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
D053614:Janus Kinase 2