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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

Possible origins of S591L mutational effects derived from the snapshots of various mutant simulations at 0 and 44 ns. Color codes are the same as in Figure 1. At the very beginning of simulations (0 ns), S591L has the same conformation as wild-type JAK2 (WT). At 44 ns, the JH1/JH2 interface is well formed in WT while L591 forms hydrophobic contacts with nearby F595, L583, and A586, totally disrupting the JH1/JH2 interface.
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Figure 6: Possible origins of S591L mutational effects derived from the snapshots of various mutant simulations at 0 and 44 ns. Color codes are the same as in Figure 1. At the very beginning of simulations (0 ns), S591L has the same conformation as wild-type JAK2 (WT). At 44 ns, the JH1/JH2 interface is well formed in WT while L591 forms hydrophobic contacts with nearby F595, L583, and A586, totally disrupting the JH1/JH2 interface.

Mentions: In our previous study, we predicted that a mutation of S591 would break the polar interaction between S591 and Q1003 and hence affect the I-1 interactions. S591L was indeed observed in MPN patients recently [34]. As shown in Figure 6, S591L has the same conformation as wild-type JAK2 at the very beginning of simulations (0 ns). At 44 ns, the JH1/JH2 interface is well formed in wild-type JAK2; in S591L JAK2, L591 forms hydrophobic contacts with nearby F595, L583, and A586. The I-1 interface is totally distorted, and the I-2 and I-3 falls apart as well. The result suggests that S591L will be a severely deleterious mutation and will cause constitutive activation of JAK2. The mechanism may reflect the hydrophobic nature of the L591 residue in that its side chain is repelled by the JH1/JH2 interface region, which is highly solvent-accessible and is surrounded with many water molecules.


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)

Possible origins of S591L mutational effects derived from the snapshots of various mutant simulations at 0 and 44 ns. Color codes are the same as in Figure 1. At the very beginning of simulations (0 ns), S591L has the same conformation as wild-type JAK2 (WT). At 44 ns, the JH1/JH2 interface is well formed in WT while L591 forms hydrophobic contacts with nearby F595, L583, and A586, totally disrupting the JH1/JH2 interface.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Possible origins of S591L mutational effects derived from the snapshots of various mutant simulations at 0 and 44 ns. Color codes are the same as in Figure 1. At the very beginning of simulations (0 ns), S591L has the same conformation as wild-type JAK2 (WT). At 44 ns, the JH1/JH2 interface is well formed in WT while L591 forms hydrophobic contacts with nearby F595, L583, and A586, totally disrupting the JH1/JH2 interface.
Mentions: In our previous study, we predicted that a mutation of S591 would break the polar interaction between S591 and Q1003 and hence affect the I-1 interactions. S591L was indeed observed in MPN patients recently [34]. As shown in Figure 6, S591L has the same conformation as wild-type JAK2 at the very beginning of simulations (0 ns). At 44 ns, the JH1/JH2 interface is well formed in wild-type JAK2; in S591L JAK2, L591 forms hydrophobic contacts with nearby F595, L583, and A586. The I-1 interface is totally distorted, and the I-2 and I-3 falls apart as well. The result suggests that S591L will be a severely deleterious mutation and will cause constitutive activation of JAK2. The mechanism may reflect the hydrophobic nature of the L591 residue in that its side chain is repelled by the JH1/JH2 interface region, which is highly solvent-accessible and is surrounded with many water molecules.

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