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Vol. 14, Issue 4, 1448-1459, April 2003
§ and
¶
*Haartman Institute, Department of Virology and
Jak tyrosine kinases have a unique domain structure containing a
kinase domain (JH1) adjacent to a catalytically inactive pseudokinase
domain (JH2). JH2 is crucial for inhibition of basal Jak activity, but
the mechanism of this regulation has remained elusive. We show that JH2
negatively regulated Jak2 in bacterial cells, indicating that
regulation is an intrinsic property of Jak2. JH2 suppressed basal Jak2
activity by lowering the Vmax of Jak2,
whereas JH2 did not affect the Km of Jak2
for a peptide substrate. Three inhibitory regions (IR1-3) within JH2
were identified. IR3 (residues 758-807), at the C terminus of JH2,
directly inhibited JH1, suggesting an inhibitory interaction between
IR3 and JH1. Molecular modeling of JH2 showed that IR3 could form a
stable Biomedicum Helsinki, Programme for Developmental
and Reproductive Biology, University of Helsinki, Helsinki FIN-00014,
Finland; Institute for Medical Technology,
University of Tampere, Tampere FIN-33014, Finland;
§Research Unit, Tampere University Hospital,
Tampere FIN-33101, Finland; and Department of
Clinical Microbiology, Tampere University Hospital, FIN-33101 Tampere,
Finland
-helical fold, supporting that IR3 could independently
inhibit JH1. IR2 (725-757) in the C-terminal lobe of JH2, and IR1
(619-670), extending from the N-terminal to the C-terminal lobe,
enhanced IR3-mediated inhibition of JH1. Disruption of IR3 either by
mutations or a small deletion increased basal Jak2 activity, but
abolished interferon-
-inducible signaling. Together, the
results provide evidence for autoinhibition of a Jak family kinase and
identify JH2 regions important for autoregulation of Jak2.
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