Sandbox Reserved 827: Difference between revisions

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Several residues of TBK1 can be modified, by phosphorylation or polyubiquitination.

'''Phosphorylation :''' <scene name='56/568025/Ser172/2'>Ser172</scene> belongs to the kinase domain and can be phosphorylated by TBK1 itself, or by another serine kinase. This phosphorylation modifies the conformation of the <scene name='56/568025/Activation_loop/1'>kinase activation loop</scene> (residues L164-G199), making the binding of the substrate possible. When S172 is not phosphorylated, the <scene name='56/568025/Hpd/1'>HPD motif</scene> can dock itself between two αhelix of the kinase domain of another promoter. Furthermore, an <scene name='56/568025/Helix/1'>helix</scene> containing the residues between D167 and L173 occupies the active site of this other protomer. Therefore, the active domain is not available for the binding of the substrate. But when S172 is phosphorylated, it can bind itself on the kinase domain of its own protomer, as the HPD domain which docks in the kinase domain in an intramolecular way, coming closer to the <scene name='56/568025/Dfg/1'>DFG</scene> domain. This liberates the active site of the other protomer, which can now bind a substrate. <ref>PMID:22619329</ref>

'''Phosphorylation :''' <scene name='56/568025/Ser172/2'>Ser172</scene> belongs to the kinase domain and can be phosphorylated by TBK1 itself, or by another serine kinase. This phosphorylation modifies the conformation of the <scene name='56/568025/Activation_loop/1'>kinase activation loop</scene> (residues L164-G199), making the binding of the substrate possible. When S172 is not phosphorylated, the <scene name='56/568025/Hpd/1'>HPD motif</scene> can dock itself between two αhelix of the kinase domain of another promoter. Furthermore, an <scene name='56/568025/Helix/1'>helix</scene> containing the residues between D167 and L173 occupies the active site of this other protomer. Therefore, the active domain is not available for the binding of the substrate. But when S172 is phosphorylated, it can bind itself on the kinase domain of its own protomer, as the HPD domain which docks in the kinase domain in an intramolecular way, coming closer to the <scene name='56/568025/Dfg/1'>DFG</scene> domain. This liberates the active site of the other protomer, which can now bind a substrate. <ref name="transact">PMID:22619329</ref>

The autophosphorylation between two subunit of a dimer is not really probable, since when the protein is dimeric, the two kinase domains are located at the opposite of one another. Therefore, the phosphorylation of Ser172 is done either by the concerned protomer, either by the kinase domain of another TBK1 dimer when TBK1 are involved in scaffolding complexes.

The autophosphorylation between two subunit of a dimer is not really probable, since when the protein is dimeric, the two kinase domains are located at the opposite of one another. Therefore, the phosphorylation of Ser172 is done either by the concerned protomer, either by the kinase domain of another TBK1 dimer when TBK1 are involved in scaffolding complexes. <ref name="transact" />

S172 can also be phosphorylated by kinases such as IKBKB or IKKB, and dephosphorylated by phosphatases such as PPM1B.

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'''Interaction with viral proteins :'''

TBK1 is the target of some viral proteins such as VP35 from Ebola virus, or the P protein from Borna virus. Those proteins inhibit TBK1. Normally, TBK1 is responsible for virus-induced phosphorylations that lead to the cellular antiviral state. Therefore, the inhibition of the kinase prevents the establishment of such a cellular state. Since TBK1 is involved into the virus entrance following reaction, targeting TBK1 is a great solution for the viruses to prevent the reactions from the cell.

TBK1 is the target of some viral proteins such as VP35 from Ebola virus <ref>PMID: 19153231</ref> , or the P protein from Borna virus. Those proteins inhibit TBK1. Normally, TBK1 is responsible for virus-induced phosphorylations that lead to the cellular antiviral state. Therefore, the inhibition of the kinase prevents the establishment of such a cellular state. Since TBK1 is involved into the virus entrance following reaction, targeting TBK1 is a great solution for the viruses to prevent the reactions from the cell.

'''Oncology :'''

Sandbox Reserved 827: Difference between revisions

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@@ Line 36: / Line 36: @@
 Several residues of TBK1 can be modified, by phosphorylation or polyubiquitination.
-'''Phosphorylation :''' <scene name='56/568025/Ser172/2'>Ser172</scene> belongs to the kinase domain and can be phosphorylated by TBK1 itself, or by another serine kinase. This phosphorylation modifies the conformation of the <scene name='56/568025/Activation_loop/1'>kinase activation loop</scene> (residues L164-G199), making the binding of the substrate possible. When S172 is not phosphorylated, the <scene name='56/568025/Hpd/1'>HPD motif</scene> can dock itself between two αhelix of the kinase domain of another promoter. Furthermore, an <scene name='56/568025/Helix/1'>helix</scene> containing the residues between D167 and L173 occupies the active site of this other protomer. Therefore, the active domain is not available for the binding of the substrate. But when S172 is phosphorylated, it can bind itself on the kinase domain of its own protomer, as the HPD domain which docks in the kinase domain in an intramolecular way, coming closer to the <scene name='56/568025/Dfg/1'>DFG</scene> domain. This liberates the active site of the other protomer, which can now bind a substrate. <ref>PMID:22619329</ref>
+'''Phosphorylation :''' <scene name='56/568025/Ser172/2'>Ser172</scene> belongs to the kinase domain and can be phosphorylated by TBK1 itself, or by another serine kinase. This phosphorylation modifies the conformation of the <scene name='56/568025/Activation_loop/1'>kinase activation loop</scene> (residues L164-G199), making the binding of the substrate possible. When S172 is not phosphorylated, the <scene name='56/568025/Hpd/1'>HPD motif</scene> can dock itself between two αhelix of the kinase domain of another promoter. Furthermore, an <scene name='56/568025/Helix/1'>helix</scene> containing the residues between D167 and L173 occupies the active site of this other protomer. Therefore, the active domain is not available for the binding of the substrate. But when S172 is phosphorylated, it can bind itself on the kinase domain of its own protomer, as the HPD domain which docks in the kinase domain in an intramolecular way, coming closer to the <scene name='56/568025/Dfg/1'>DFG</scene> domain. This liberates the active site of the other protomer, which can now bind a substrate. <ref name="transact">PMID:22619329</ref>
-The autophosphorylation between two subunit of a dimer is not really probable, since when the protein is dimeric, the two kinase domains are located at the opposite of one another. Therefore, the phosphorylation of Ser172 is done either by the concerned protomer, either by the kinase domain of another TBK1 dimer when TBK1 are involved in scaffolding complexes.
+The autophosphorylation between two subunit of a dimer is not really probable, since when the protein is dimeric, the two kinase domains are located at the opposite of one another. Therefore, the phosphorylation of Ser172 is done either by the concerned protomer, either by the kinase domain of another TBK1 dimer when TBK1 are involved in scaffolding complexes. <ref name="transact" />
 S172 can also be phosphorylated by kinases such as IKBKB or IKKB, and dephosphorylated by phosphatases such as PPM1B.
@@ Line 55: / Line 55: @@
 '''Interaction with viral proteins :'''
-TBK1 is the target of some viral proteins such as VP35 from Ebola virus, or the P protein from Borna virus. Those proteins inhibit TBK1. Normally, TBK1 is responsible for virus-induced phosphorylations that lead to the cellular antiviral state. Therefore, the inhibition of the kinase prevents the establishment of such a cellular state. Since TBK1 is involved into the virus entrance following reaction, targeting TBK1 is a great solution for the viruses to prevent the reactions from the cell.
+TBK1 is the target of some viral proteins such as VP35 from Ebola virus <ref>PMID: 19153231</ref> , or the P protein from Borna virus. Those proteins inhibit TBK1. Normally, TBK1 is responsible for virus-induced phosphorylations that lead to the cellular antiviral state. Therefore, the inhibition of the kinase prevents the establishment of such a cellular state. Since TBK1 is involved into the virus entrance following reaction, targeting TBK1 is a great solution for the viruses to prevent the reactions from the cell.
 '''Oncology :'''