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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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Related in: MedlinePlus

Heavy atom root-mean-squared deviation (RMSD, in Å, relative to the initial structure) of JH1 domain (defined as residue 840 to 1129), JH2 domain (defined as residue 543 to 839), and of JH1/JH2 together (defined as residue 543 to 1129) for the wild-type JAK2.
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Figure 10: Heavy atom root-mean-squared deviation (RMSD, in Å, relative to the initial structure) of JH1 domain (defined as residue 840 to 1129), JH2 domain (defined as residue 543 to 839), and of JH1/JH2 together (defined as residue 543 to 1129) for the wild-type JAK2.

Mentions: Figure 10 shows the heavy atom root-mean-squared deviation (RMSD, in Å, relative to the initial strucuture) of JH1 domain (defined as residue 840 to 1129), JH2 domain (defined as residue 543 to 839), and of JH1/JH2 together (defined as residue 543 to 1129) for the wild-type JAK2. RMSD is commonly used as an indicator of stability of MD simulations. The RMSD curves of individual JH1 and JH2 domains indicate simulations of both domains are stable after ~20 ns. The RMSD curve of combined JH1/JH2 indicates that the relative positions of JH1/JH2 as well as their tertiary interactions are also stable after ~20 ns. Simulations of other mutants exhibit similar behaviours. Those results suggest that the simulations reported here are converged and the corresponding derived analysis is reliable in the timescale simulated.


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)

Heavy atom root-mean-squared deviation (RMSD, in Å, relative to the initial structure) of JH1 domain (defined as residue 840 to 1129), JH2 domain (defined as residue 543 to 839), and of JH1/JH2 together (defined as residue 543 to 1129) for the wild-type JAK2.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 10: Heavy atom root-mean-squared deviation (RMSD, in Å, relative to the initial structure) of JH1 domain (defined as residue 840 to 1129), JH2 domain (defined as residue 543 to 839), and of JH1/JH2 together (defined as residue 543 to 1129) for the wild-type JAK2.
Mentions: Figure 10 shows the heavy atom root-mean-squared deviation (RMSD, in Å, relative to the initial strucuture) of JH1 domain (defined as residue 840 to 1129), JH2 domain (defined as residue 543 to 839), and of JH1/JH2 together (defined as residue 543 to 1129) for the wild-type JAK2. RMSD is commonly used as an indicator of stability of MD simulations. The RMSD curves of individual JH1 and JH2 domains indicate simulations of both domains are stable after ~20 ns. The RMSD curve of combined JH1/JH2 indicates that the relative positions of JH1/JH2 as well as their tertiary interactions are also stable after ~20 ns. Simulations of other mutants exhibit similar behaviours. Those results suggest that the simulations reported here are converged and the corresponding derived analysis is reliable in the timescale simulated.

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