Tank-binding kinase 1–Optineurin protein-protein interface (TBK1–OPTN interface)

The TBK1–Optineurin protein-protein interface is the molecular contact site where TBK1 (Tank-binding kinase 1), an essential serine/threonine kinase, interacts with Optineurin (OPTN), a regulatory adaptor involved in selective autophagy, mitophagy, and immune signaling. This interface consists of the N-terminal coiled-coil domain of OPTN binding to the C-terminal domain of TBK1, forming a complex essential for the recruitment and activation of TBK1 at damaged organelles or aggregates[1][2][4][7][8]. The complex formation is crucial for promoting downstream autophagy, phosphorylating OPTN, and amplifying autophagic clearance signals. Mutations at or near this interface are linked to familial forms of amyotrophic lateral sclerosis, glaucoma, and other neurodegenerative diseases[1][4][6], underscoring its relevance as a disease mechanism and as a potential therapeutic target. While TBK1 kinase inhibitors have been studied preclinically, targeting the protein-protein interface itself remains a frontier for novel drug discovery approaches[2][3].

Other names

TBK1–Optineurin complexTBK1/OPTN binding interfaceTBK1–OPTN interaction

Inhibition of interaction: Blocking the interface disrupts autophagy signaling, as shown by engineered monobodies against OPTN that block TBK1 activation. TBK1 kinase inhibition: Small molecules inhibit phosphorylation of OPTN or other adaptors, affecting mitophagy and inflammatory signaling. Allosteric modulation: Experimental molecules that interfere with TBK1 recruitment, binding or activation via OPTN (preclinical only).