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Structural effects of clinically observed mutations in JAK2 exons 13-15: comparison with V617F and exon 12 mutations.

Lee TS, Ma W, Zhang X, Kantarjian H, Albitar M - BMC Struct. Biol. (2009)

Bottom Line: Simulation results are consistent with all currently available clinical/experimental evidence.The simulation-derived putative interface, not possibly obtained from static models, between the kinase (JH1) and pseudokinase (JH2) domains of JAK2 provides a platform able to explain the mutational effect for all mutants, including presumably benign control mutants, at the atomic level.The results and analysis provide structural bases for mutational mechanisms of JAK2, may advance the understanding of JAK2 auto-regulation, and have the potential to lead to therapeutic approaches.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biomedical Informatics and Computational Biology, and Department of Chemistry, University of Minnesota, 207 Pleasant Street, S.E., Minneapolis, MN 55455, USA. leex2750@umn.edu

ABSTRACT

Background: The functional relevance of many of the recently detected JAK2 mutations, except V617F and exon 12 mutants, in patients with chronic myeloproliferative neoplasia (MPN) has been significantly overlooked. To explore atomic-level explanations of the possible mutational effects from those overlooked mutants, we performed a set of molecular dynamics simulations on clinically observed mutants, including newly discovered mutations (K539L, R564L, L579F, H587N, S591L, H606Q, V617I, V617F, C618R, L624P, whole exon 14-deletion) and control mutants (V617C, V617Y, K603Q/N667K).

Results: Simulation results are consistent with all currently available clinical/experimental evidence. The simulation-derived putative interface, not possibly obtained from static models, between the kinase (JH1) and pseudokinase (JH2) domains of JAK2 provides a platform able to explain the mutational effect for all mutants, including presumably benign control mutants, at the atomic level.

Conclusion: The results and analysis provide structural bases for mutational mechanisms of JAK2, may advance the understanding of JAK2 auto-regulation, and have the potential to lead to therapeutic approaches. Together with recent mutation profiling results demonstrating the breadth of clinically observed JAK2 mutations, our findings suggest that molecular testing/diagnostics of JAK2 should extend beyond V617F and exon 12 mutations, and perhaps should encompass most of the pseudo-kinase domain-coding region.

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The relative torsion angle between the JH1 C-helix and the JH2 C-helix. This angle is defined as the dihedral angle between the carbonyl carbon atoms of residues R893, E900, S599, and E592. Data across the bottom of the figure indicate the difference in torsion of each mutant relative to the average torsion of the wild-type JAK2 simulation (-5.71 degrees). Mutations with larger relative torsion angles exhibit greater deviation from wild-type JAK2 and are thus more likely to be deleterious. The error bars are the standard deviations of the calculated values from the last 30-ns trajectory for each mutant. Entries were obtained with a sampling frequency of 10 ps; i.e., 3,000 sample data points for each mutant simulation.
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Figure 3: The relative torsion angle between the JH1 C-helix and the JH2 C-helix. This angle is defined as the dihedral angle between the carbonyl carbon atoms of residues R893, E900, S599, and E592. Data across the bottom of the figure indicate the difference in torsion of each mutant relative to the average torsion of the wild-type JAK2 simulation (-5.71 degrees). Mutations with larger relative torsion angles exhibit greater deviation from wild-type JAK2 and are thus more likely to be deleterious. The error bars are the standard deviations of the calculated values from the last 30-ns trajectory for each mutant. Entries were obtained with a sampling frequency of 10 ps; i.e., 3,000 sample data points for each mutant simulation.

Mentions: The use of various distances between JH1 and JH2 proved useful in characterizing the JH1/JH2 interface in our previous work [42]. However, the large number of distances needed to monitor the JH1/JH2 interface makes a succinct summary of the results difficult. Hence, instead of inter-atomic distances, we used the torsion angle between the C-helices of JH1 and JH2 to monitor the I-1 group of interactions. Figure 3 shows the relative torsion angle, defined as the dihedral angle between the carbonyl carbon atoms of residues R893, E900, S599, and E592, of all mutants from simulations,. I-1 interactions are severely changed in four mutants: K539L, S591L, V617I, and C618R. The data for 14-del is not shown since this mutant lacks the entire JH2 C-helix. I-1 interactions are more-or-less maintained in four mutants: L579F, K603N667K, V617C, and V617Y.


Structural effects of clinically observed mutations in JAK2 exons 13-15: comparison with V617F and exon 12 mutations.

Lee TS, Ma W, Zhang X, Kantarjian H, Albitar M - BMC Struct. Biol. (2009)

The relative torsion angle between the JH1 C-helix and the JH2 C-helix. This angle is defined as the dihedral angle between the carbonyl carbon atoms of residues R893, E900, S599, and E592. Data across the bottom of the figure indicate the difference in torsion of each mutant relative to the average torsion of the wild-type JAK2 simulation (-5.71 degrees). Mutations with larger relative torsion angles exhibit greater deviation from wild-type JAK2 and are thus more likely to be deleterious. The error bars are the standard deviations of the calculated values from the last 30-ns trajectory for each mutant. Entries were obtained with a sampling frequency of 10 ps; i.e., 3,000 sample data points for each mutant simulation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2749040&req=5

Figure 3: The relative torsion angle between the JH1 C-helix and the JH2 C-helix. This angle is defined as the dihedral angle between the carbonyl carbon atoms of residues R893, E900, S599, and E592. Data across the bottom of the figure indicate the difference in torsion of each mutant relative to the average torsion of the wild-type JAK2 simulation (-5.71 degrees). Mutations with larger relative torsion angles exhibit greater deviation from wild-type JAK2 and are thus more likely to be deleterious. The error bars are the standard deviations of the calculated values from the last 30-ns trajectory for each mutant. Entries were obtained with a sampling frequency of 10 ps; i.e., 3,000 sample data points for each mutant simulation.
Mentions: The use of various distances between JH1 and JH2 proved useful in characterizing the JH1/JH2 interface in our previous work [42]. However, the large number of distances needed to monitor the JH1/JH2 interface makes a succinct summary of the results difficult. Hence, instead of inter-atomic distances, we used the torsion angle between the C-helices of JH1 and JH2 to monitor the I-1 group of interactions. Figure 3 shows the relative torsion angle, defined as the dihedral angle between the carbonyl carbon atoms of residues R893, E900, S599, and E592, of all mutants from simulations,. I-1 interactions are severely changed in four mutants: K539L, S591L, V617I, and C618R. The data for 14-del is not shown since this mutant lacks the entire JH2 C-helix. I-1 interactions are more-or-less maintained in four mutants: L579F, K603N667K, V617C, and V617Y.

Bottom Line: Simulation results are consistent with all currently available clinical/experimental evidence.The simulation-derived putative interface, not possibly obtained from static models, between the kinase (JH1) and pseudokinase (JH2) domains of JAK2 provides a platform able to explain the mutational effect for all mutants, including presumably benign control mutants, at the atomic level.The results and analysis provide structural bases for mutational mechanisms of JAK2, may advance the understanding of JAK2 auto-regulation, and have the potential to lead to therapeutic approaches.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biomedical Informatics and Computational Biology, and Department of Chemistry, University of Minnesota, 207 Pleasant Street, S.E., Minneapolis, MN 55455, USA. leex2750@umn.edu

ABSTRACT

Background: The functional relevance of many of the recently detected JAK2 mutations, except V617F and exon 12 mutants, in patients with chronic myeloproliferative neoplasia (MPN) has been significantly overlooked. To explore atomic-level explanations of the possible mutational effects from those overlooked mutants, we performed a set of molecular dynamics simulations on clinically observed mutants, including newly discovered mutations (K539L, R564L, L579F, H587N, S591L, H606Q, V617I, V617F, C618R, L624P, whole exon 14-deletion) and control mutants (V617C, V617Y, K603Q/N667K).

Results: Simulation results are consistent with all currently available clinical/experimental evidence. The simulation-derived putative interface, not possibly obtained from static models, between the kinase (JH1) and pseudokinase (JH2) domains of JAK2 provides a platform able to explain the mutational effect for all mutants, including presumably benign control mutants, at the atomic level.

Conclusion: The results and analysis provide structural bases for mutational mechanisms of JAK2, may advance the understanding of JAK2 auto-regulation, and have the potential to lead to therapeutic approaches. Together with recent mutation profiling results demonstrating the breadth of clinically observed JAK2 mutations, our findings suggest that molecular testing/diagnostics of JAK2 should extend beyond V617F and exon 12 mutations, and perhaps should encompass most of the pseudo-kinase domain-coding region.

Show MeSH
Related in: MedlinePlus