Sandbox Reserved 827: Difference between revisions
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<Structure load='4IW0' size='430' frame='true' align='right' caption='TBK1 monomer (PDB entry 4IW0)' scene='56/568025/Vide/1' /> | <Structure load='4IW0' size='430' frame='true' align='right' caption='TBK1 monomer (PDB entry 4IW0)' scene='56/568025/Vide/1' /> | ||
==Protomer== | ==Protomer== | ||
[[Image:Lobes.jpg|400px|left|thumb| Structure of the KD domain in TBK1.]] | |||
'''Kinase domain :''' (<scene name='56/568025/Kd/1'>KD</scene>) from amino acid 9 to amino acid 310: the active site is at the interface of the N- and C-terminal lobes. | '''Kinase domain :''' (<scene name='56/568025/Kd/1'>KD</scene>) from amino acid 9 to amino acid 310: the active site is at the interface of the N- and C-terminal lobes. | ||
Inactive conformation: the C-helix and key residue Glu55 displaced from the active site. | Inactive conformation: the C-helix and key residue Glu55 displaced from the active site. | ||
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Several residues of TBK1 can be modified, by phosphorylation or polyubiquitination. | 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 name="transact">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> | ||
[[Image:Dimere.jpg|400px|left|thumb| When S172 isn't phosphorylated, the activation loop binds to the active site of another protomer, providing the phosphorylation of substrates.]] | |||
[[Image:Activationloop.jpg|400px|center|thumb| When S172 is phosphorylated, the activation loop comes closer to the KD, thanks to the docking of HPD. One protomer is in blue, the other in orange.]] | |||
[[Image:transactivation.jpg|400px|left|thumb| Hypothecal diagram of the transactivation mechanism of TBK1.]] | |||
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" /> | 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 IKKB (also known as IKBKB), and dephosphorylated by phosphatases such as PPM1B. | S172 can also be phosphorylated by kinases such as IKKB (also known as IKBKB), and dephosphorylated by phosphatases such as PPM1B. | ||
'''Polyubiquitination :''' Polyubiquitination in a Lys63 manner on | '''Polyubiquitination :''' Polyubiquitination in a Lys63 manner on | ||
<scene name='56/568025/K30/1'>Lys30</scene> helps the activation of the kinase. The same type of modification on <scene name='56/568025/K401/1'>Lys401</scene> is responsible for dimerization. Type Lys48 polyubiquitination on Lys670 is done by DTX4 and is responsible for the degradation of the protein. | <scene name='56/568025/K30/1'>Lys30</scene> helps the activation of the kinase. The same type of modification on <scene name='56/568025/K401/1'>Lys401</scene> is responsible for dimerization. | ||
Type Lys48 polyubiquitination on Lys670 is done by DTX4 and is responsible for the degradation of the protein, since this type of polyubiquitination is recognized by the proteasome. | |||
= Signalling pathways = | = Signalling pathways = | ||
