RT Journal Article
SR Electronic
T1 Structural models of full-length JAK2 kinase
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 727727
DO 10.1101/727727
A1 Pelin Ayaz
A1 Henrik M. Hammarén
A1 Juuli Raivola
A1 Dina Sharon
A1 Stevan R. Hubbard
A1 Olli Silvennoinen
A1 Yibing Shan
A1 David E. Shaw
YR 2019
UL http://biorxiv.org/content/early/2019/08/07/727727.abstract
AB The protein JAK2 is a prototypical member of the Janus kinase family, and mediates signals from numerous cytokine receptors. The constitutively active V617F mutant of JAK2 is prevalent in many bone marrow disorders, blood cancers, and autoimmune diseases, and is an important drug target. Structures have been determined for each of the four individual domains making up JAK2, and for certain pairs of these domains, but no structure of full-length JAK2 is available, and thus the mechanisms underlying JAK2 regulation and the aberrant activity of the V617F mutant have been incompletely understood. Here we propose structural models of full-length JAK2 in both its active and inactive forms. Construction of these models was informed by long-timescale molecular dynamics simulations. Subsequent mutagenesis experiments showed that mutations at the putative interdomain interfaces modulated JAK2 activity. The models provide a structural basis for understanding JAK2 autoinhibition and activation, and suggest that the constitutive activity of the V617F mutant may arise from a dual effect of destabilizing the inactive conformation and stabilizing the active conformation.