Sandbox Reserved 827: Difference between revisions
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<Structure load='4IM3' size='400' frame='true' align='right' caption='TBK1' scene='Insert optional scene name here' /> | <Structure load='4IM3' size='400' frame='true' align='right' caption='TBK1' scene='Insert optional scene name here' /> | ||
= | = Overall structure = | ||
==Protomer== | ==Protomer== | ||
'''Kinase domain :''' | '''Kinase domain :''' (KD) 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. | |||
Active conformation: a rotation of the C-helix allows a key salt-bridge interaction between conserved glutamic acid in the C-helix and an active-site lysine residue. | |||
The DFG (Asp-Phe-Gly) motif and Ser172 are involved in the regulation of the kinase activity. | |||
''' | '''Ubiquitin-like domain :''' (ULD) from amino acid 309 to amino acid 385: it contains five β strands which form a hydrophobic interface. | ||
'''Leucine zipper :''' | '''Leucine zipper :''' between amino acid 408 and amino acid 651 | ||
'''Coiled coil :''' | '''Coiled coil :''' between amino acid 408 and amino acid 651 | ||
'''ATP binding domain :''' from amino acid 15 to amino acid 23. | |||
The KD and the ULD interact with each other: the ULD with the C-lobe of the KD. There is a hydrogen bond between Tyr325 in the ULD and Glu109 in the KD. Moreover Lys323 in the ULD makes favourable electrostatic interactions with Glu109-KD. | |||
==Dimer== | ==Dimer== | ||
ULD and KD also contribute to dimerization thanks to several interactions with the SDD of the opposite subunit in the homodimer. | |||
There are several hydrogen bonds between the KD (N- and C-lobes) and the SDD of the opposite subunit: a salt bridge is formed between Asp33 in the N-lobe and Lys589 in the SDD and the strands the β7-β8 in the C-love interact with the SDD. A “EGR” sequence (residues 355–357) in the ULD interacts with the SDD: Glu355-ULD interacts with Arg444-SDD (salt bridge) and Trp445-SDD (hydrogen bonds). | |||
= Possible residue modifications = | = Possible residue modifications = | ||
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<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. | ||
= Signalling pathways = | |||
== Inflammatory response == | |||
The inflammatory response begin with the formation of the complex TBK1-TANK-TRAF. That allows phosphorylation of IRF3, IRF7 and DDX3X. Then these phosphorylated proteins form homodimers and they are translocated into the nucleus, where they activate transcription of interferon regulatory factors (IFN). | |||
== Anti-apoptosis == | |||
And the complex phosphorylates an inhibitor of NFkappaB, which finally activates NFkappaB, an anti-apoptotic transcription factor. | |||
= Diseases = | = Diseases = | ||
