NDLI: A shift in the salt bridge interaction of residues D620 and E621 mediates the constitutive activation of Jak2-H538Q/K539L

Content Provider	Springer Nature Link
Author	Gnanasambandan, Kavitha Magis, Andrew T. Sayeski, Peter P.
Copyright Year	2012
Abstract	Jak2 mutations in the exon 14 and exon 12 regions that cause constitutive activation have been associated with myeloproliferative neoplasms. We have previously shown that a pi stacking interaction between F617 and F595 is important for the constitutive activation of Jak2-V617F (Gnanasambandan et al., Biochemistry 49:9972–9984, 2010). Here, using a combination of molecular dynamics (MD) simulations and in vitro mutagenesis, we studied the molecular mechanism for the constitutive activation of the Jak2 exon 12 mutation, H538Q/K539L. The activation levels of Jak2-H538Q/K539L were found to be similar to that of Jak2-V617F, and Jak2-H538Q/K539L/V617F. Data from MD simulations indicated a shift in the salt bridge interactions of D620 and E621 with K539 in Jak2-WT to R541 in Jak2-H538Q/K539L. When compared to Jak2-WT, K539A mutation resulted in increased activation, while K539D or K539E mutations diminished Jak2 activation by 50 %. In the context of Jak2-H538Q/K539L, R541A mutation reduced its activation by 50 %, while R541D and R541E mutations returned its activation levels to that of Jak2-WT. Collectively, these results indicate that a shift in the salt bridge interaction of D620 and E621 with K539 in Jak2-WT to R541 in Jak2-H538Q/K539L is critical for constitutive activation of this Jak2 exon 12 mutant.
Starting Page	125
Ending Page	140
Page Count	16
File Format	PDF
ISSN	03008177
Journal	Molecular and Cellular Biochemistry
Volume Number	367
Issue Number	1-2
e-ISSN	15734919
Language	English
Publisher	Springer US
Publisher Date	2012-05-15
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Jak2 Exon 12 mutation MPNs Salt bridge Simulations Mechanism Medical Biochemistry Cardiology Oncology Biochemistry
Content Type	Text
Resource Type	Article
Subject	Cell Biology Medicine Clinical Biochemistry Molecular Biology

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