==Protomer==

Kinase domain : ( ) 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 : ( ) from amino acid 309 to amino acid 385: it contains five β strands which form a hydrophobic interface.

 : between amino acid 408 and amino acid 651

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

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

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

Phosphorylation : belongs to the kinase domain and can be phosphorylated by TBK1 itself, or by another serine kinase. This phosphorylation modifies the conformation of the (residues L164-G199), making the binding of the substrate possible. When S172 is not phosphorylated, the can dock itself between two αhelix of the kinase domain of another promoter. Furthermore, an 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 domain. This liberates the active site of the other protomer, which can now bind a substrate. ^[1]

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. ^[1] S172 can also be phosphorylated by kinases such as IKBKB or IKKB, and dephosphorylated by phosphatases such as PPM1B.

Polyubiquitination : Polyubiquitination in a Lys63 manner on

helps the activation of the kinase. The same type of modification on is responsible for dimerization. Type Lys48 polyubiquitination on Lys670 is done by DTX4 and is responsible for the degradation of the protein.