Sandbox Reserved 598: Difference between revisions

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[[Image:Jak2B.png|thumb|200px|center|Figure 2]]

[[Image:Jak2C.png|thumb|200px|right|Figure 3]]

In the unbound and inactive state of Jak2, the FERM (JH4-7), JH1 (kinase domain) and JH2 (pseduokinase domain) domains of are tightly folded together preventing the catalytic domain from being active. (Figure 1) However, the first activation step of Jak2 is the displacement of the FERM domain by its interaction with the receptor which begins the unfolding of domains within the protein to allow access to the various binding domains. (Figure 2). In the presence of a ligand, receptor aggregation occurs. As a result of this aggregation, the tyrosine within the Jak2 active loop is phosphorylated and then induces changes in both JH2 and JH1 domains. Once phosphorylation occurs within the activation loop, the kinase is fully activated. (Figure 3) {Figures 1-3 from (Funakoshi-Tago, 2008) Under normal conditions, Jak2 is not associated with a receptor and is locked into an inactive state. Receptor binding through the FERM domain relieves steric constraints, and allows Jak2 to be activated once it is engaged with its erythropoietin receptor. Activation of Jak2 by erythropoietin receptor engagement leads to the tyrosine phosphorylation of the receptor and Jak2. <ref> Funakoshi-Tago, M., Pelletier, S., & Moritake, H. (2008). Jak2 ferm domain interaction with the erythropoietin receptor regulates jak2 kinase activity. Molecular and Cellular Biology, 28(5), 1792-1801. doi: 10.1128/MCB.01447-07 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2258779/ </ref>

In the unbound and inactive state of Jak2, the FERM (JH4-7), JH1 (kinase domain) and JH2 (pseduokinase domain) domains of are tightly folded together preventing the catalytic domain from being active. (Figure 1) However, the first activation step of Jak2 is the displacement of the FERM domain by its interaction with the receptor which begins the unfolding of domains within the protein to allow access to the various binding domains. (Figure 2). In the presence of a ligand, receptor aggregation occurs. As a result of this aggregation, the tyrosine within the Jak2 active loop is phosphorylated and then induces changes in both JH2 and JH1 domains. Once phosphorylation occurs within the activation loop, the kinase is fully activated. (Figure 3) {Figures 1-3 from (Funakoshi-Tago, 2008)} Under normal conditions, Jak2 is not associated with a receptor and is locked into an inactive state. Receptor binding through the FERM domain relieves steric constraints, and allows Jak2 to be activated once it is engaged with its erythropoietin receptor. Activation of Jak2 by erythropoietin receptor engagement leads to the tyrosine phosphorylation of the receptor and Jak2. <ref> Funakoshi-Tago, M., Pelletier, S., & Moritake, H. (2008). Jak2 ferm domain interaction with the erythropoietin receptor regulates jak2 kinase activity. Molecular and Cellular Biology, 28(5), 1792-1801. doi: 10.1128/MCB.01447-07 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2258779/ </ref>

[[Image:Jak2Mutation.png|thumb|250px|left|Figure 4]]

Mutations in Jak2 can result in the erythropoietin receptor being activated all the time. Due to lack of auto-inhibition of the JAK2 enzyme because of this activating mutation the receptor is effectively switched to the ‘on’ position indefinitely, constantly over-produce cells. This type of mutation has been found to occur in a nucleotide substitution of valine to phenylalanine and is therefore termed, V617F. The active conformation of Jak2 is likely to be mimicked by the Jak2-V617F mutant and this thereby results in either oncogenesis, polycythemia or other hematopoietic disorders. <ref>Gnanasambandan, K., & Sayeski, P. (2011). A structure-function perspective of jak2 mutations and implications for alternate drug design strategies: the road not taken. Department of Physiology and Functional Genomics, University of Florida College of Medicine, 18(30), 59-73. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21864276 http://www.ncbi.nlm.nih.gov/pubmed/21864276 </ref> Other mutant conformations, such as the Y613E mutant, failed to undergo complete conformational changes leading to its activation. <ref> Funakoshi-Tago, M., Pelletier, S., & Moritake, H. (2008). Jak2 ferm domain interaction with the erythropoietin receptor regulates jak2 kinase activity. Molecular and Cellular Biology, 28(5), 1792-1801. doi: 10.1128/MCB.01447-07 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2258779/

(7) Kirwan, J. (02, 2011 03). Janus incarnate. Retrieved from http://rense.com/general92/janus.htm </ref> A diagramed example of how normal Jak2 receptors work, as well as how this mutation works mechanically can be seen on figure 4.

(7) Kirwan, J. (02, 2011 03). Janus incarnate. Retrieved from http://rense.com/general92/janus.htm </ref> A diagramed example of how normal Jak2 receptors work, as well as how this mutation works mechanically can be seen on figure 4 which was from (Gnanasambandan,2005).

[[Image:Jak2DNA.png|thumb|250px|left|Figure 5]] Figure 5 shows the amino acid sequence alignment of JAK2 along with the other members of the JAK family TYK2, JAK3, and JAK1 and the kinase domain of FAK and LCK around the Lip region. Cylinders show alpha-helices, the residues conserved among the JAK kinases sequence are highlighted in red. The dark gray boxes indicate which residues are conserved to at least 75% within the janus kinase family and finally the light gray boxes indicate conservatively substituted residues. <ref> ) Lucet, I., Fantino, E., & Styles, M. (2005). The structural basis of janus kinase 2 inhibition by a potent and specific pan-janus kinase inhibitor. Blood, 107, 176-183. doi: 10.1182/blood-2005-06-2413 http://bloodjournal.hematologylibrary.org/content/107/1/176.full.pdf </ref>

[[Image:Jak2DNA.png|thumb|250px|left|Figure 5]] Figure 5 shows the amino acid sequence alignment of JAK2 along with the other members of the JAK family TYK2, JAK3, and JAK1 and the kinase domain of FAK and LCK around the Lip region (Lucet, 2011). Cylinders show alpha-helices, the residues conserved among the JAK kinases sequence are highlighted in red. The dark gray boxes indicate which residues are conserved to at least 75% within the janus kinase family and finally the light gray boxes indicate conservatively substituted residues. <ref> ) Lucet, I., Fantino, E., & Styles, M. (2005). The structural basis of janus kinase 2 inhibition by a potent and specific pan-janus kinase inhibitor. Blood, 107, 176-183. doi: 10.1182/blood-2005-06-2413 http://bloodjournal.hematologylibrary.org/content/107/1/176.full.pdf </ref>

== Conditions Associated with Jak2 Mutations ==

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@@ Line 27: / Line 27: @@
 [[Image:Jak2B.png|thumb|200px|center|Figure 2]]
 [[Image:Jak2C.png|thumb|200px|right|Figure 3]]
-In the unbound and inactive state of Jak2, the FERM (JH4-7), JH1 (kinase domain) and JH2 (pseduokinase domain) domains of are tightly folded together preventing the catalytic domain from being active. (Figure 1)  However, the first activation step of  Jak2 is the displacement of the FERM domain by its interaction with the receptor which begins the unfolding of domains within the protein to allow access to the various binding domains. (Figure 2). In the presence of a ligand, receptor aggregation occurs. As a result of this aggregation, the tyrosine within the Jak2 active loop is phosphorylated and then induces changes in both JH2 and JH1 domains. Once phosphorylation occurs within the activation loop, the kinase is fully activated. (Figure 3) {Figures 1-3 from (Funakoshi-Tago, 2008) Under normal conditions, Jak2 is not associated with a receptor and is locked into an inactive state. Receptor binding through the FERM domain relieves steric constraints, and allows Jak2 to be activated once it is engaged with its erythropoietin receptor. Activation of Jak2 by erythropoietin receptor engagement leads to the tyrosine phosphorylation of the receptor and Jak2. <ref> Funakoshi-Tago, M., Pelletier, S., & Moritake, H. (2008). Jak2 ferm domain interaction with the erythropoietin receptor regulates jak2 kinase activity. Molecular and Cellular Biology, 28(5), 1792-1801. doi: 10.1128/MCB.01447-07  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2258779/ </ref>
+In the unbound and inactive state of Jak2, the FERM (JH4-7), JH1 (kinase domain) and JH2 (pseduokinase domain) domains of are tightly folded together preventing the catalytic domain from being active. (Figure 1)  However, the first activation step of  Jak2 is the displacement of the FERM domain by its interaction with the receptor which begins the unfolding of domains within the protein to allow access to the various binding domains. (Figure 2). In the presence of a ligand, receptor aggregation occurs. As a result of this aggregation, the tyrosine within the Jak2 active loop is phosphorylated and then induces changes in both JH2 and JH1 domains. Once phosphorylation occurs within the activation loop, the kinase is fully activated. (Figure 3) {Figures 1-3 from (Funakoshi-Tago, 2008)} Under normal conditions, Jak2 is not associated with a receptor and is locked into an inactive state. Receptor binding through the FERM domain relieves steric constraints, and allows Jak2 to be activated once it is engaged with its erythropoietin receptor. Activation of Jak2 by erythropoietin receptor engagement leads to the tyrosine phosphorylation of the receptor and Jak2. <ref> Funakoshi-Tago, M., Pelletier, S., & Moritake, H. (2008). Jak2 ferm domain interaction with the erythropoietin receptor regulates jak2 kinase activity. Molecular and Cellular Biology, 28(5), 1792-1801. doi: 10.1128/MCB.01447-07  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2258779/ </ref>
 [[Image:Jak2Mutation.png|thumb|250px|left|Figure 4]]
 Mutations in Jak2 can result in the erythropoietin receptor being activated all the time. Due to lack of auto-inhibition of the JAK2 enzyme because of  this activating mutation the receptor is effectively switched to the ‘on’ position indefinitely, constantly over-produce cells. This type of mutation has been found to occur in a nucleotide substitution of valine to phenylalanine and is therefore termed, V617F. The active conformation of Jak2 is likely to be mimicked by the Jak2-V617F mutant and this thereby results in either oncogenesis, polycythemia or other hematopoietic disorders. <ref>Gnanasambandan, K., & Sayeski, P. (2011). A structure-function perspective of jak2 mutations and implications for alternate drug design strategies: the road not taken. Department of Physiology and Functional Genomics, University of Florida College of Medicine, 18(30), 59-73. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21864276 http://www.ncbi.nlm.nih.gov/pubmed/21864276 </ref> Other mutant conformations, such as the Y613E mutant, failed to undergo complete conformational changes leading to its activation. <ref> Funakoshi-Tago, M., Pelletier, S., & Moritake, H. (2008). Jak2 ferm domain interaction with the erythropoietin receptor regulates jak2 kinase activity. Molecular and Cellular Biology, 28(5), 1792-1801. doi: 10.1128/MCB.01447-07  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2258779/
-(7) Kirwan, J. (02, 2011 03). Janus incarnate. Retrieved from http://rense.com/general92/janus.htm  </ref> A diagramed example of how normal Jak2 receptors work, as well as how this mutation works mechanically can be seen on figure 4.
+(7) Kirwan, J. (02, 2011 03). Janus incarnate. Retrieved from http://rense.com/general92/janus.htm  </ref> A diagramed example of how normal Jak2 receptors work, as well as how this mutation works mechanically can be seen on figure 4 which was from (Gnanasambandan,2005).
-[[Image:Jak2DNA.png|thumb|250px|left|Figure 5]] Figure 5 shows the amino acid sequence alignment of JAK2 along with the other members of the JAK family TYK2, JAK3, and JAK1 and the kinase domain of FAK and LCK around the Lip region. Cylinders show alpha-helices, the residues  conserved among the JAK kinases sequence are highlighted in red. The dark gray boxes indicate which residues are conserved to at least 75% within the janus kinase family and finally the light gray boxes indicate conservatively substituted residues. <ref> ) Lucet, I., Fantino, E., & Styles, M. (2005). The structural basis of janus kinase 2 inhibition by a potent and specific pan-janus kinase inhibitor. Blood, 107, 176-183. doi: 10.1182/blood-2005-06-2413 http://bloodjournal.hematologylibrary.org/content/107/1/176.full.pdf </ref>
+[[Image:Jak2DNA.png|thumb|250px|left|Figure 5]] Figure 5 shows the amino acid sequence alignment of JAK2 along with the other members of the JAK family TYK2, JAK3, and JAK1 and the kinase domain of FAK and LCK around the Lip region (Lucet, 2011). Cylinders show alpha-helices, the residues  conserved among the JAK kinases sequence are highlighted in red. The dark gray boxes indicate which residues are conserved to at least 75% within the janus kinase family and finally the light gray boxes indicate conservatively substituted residues. <ref> ) Lucet, I., Fantino, E., & Styles, M. (2005). The structural basis of janus kinase 2 inhibition by a potent and specific pan-janus kinase inhibitor. Blood, 107, 176-183. doi: 10.1182/blood-2005-06-2413 http://bloodjournal.hematologylibrary.org/content/107/1/176.full.pdf </ref>
 == Conditions Associated with Jak2 Mutations ==