Abstract
Optineurin is an important autophagy receptor involved in several selective autophagy processes, during which its function is regulated by TBK1. Mutations of optineurin and TBK1 are both associated with neurodegenerative diseases. However, the mechanistic basis underlying the specific interaction between optineurin and TBK1 is still elusive. Here we determine the crystal structures of optineurin/TBK1 complex and the related NAP1/TBK1 complex, uncovering the detailed molecular mechanism governing the optineurin and TBK1 interaction, and revealing a general binding mode between TBK1 and its associated adaptor proteins. In addition, we demonstrate that the glaucoma-associated optineurin E50K mutation not only enhances the interaction between optineurin and TBK1 but also alters the oligomeric state of optineurin, and the ALS-related TBK1 E696K mutation specifically disrupts the optineurin/TBK1 complex formation but has little effect on the NAP1/TBK1 complex. Thus, our study provides mechanistic insights into those currently known disease-causing optineurin and TBK1 mutations found in patients.
Highlights
Optineurin is an important autophagy receptor involved in several selective autophagy processes, during which its function is regulated by TANK-binding kinase 1 (TBK1)
Our results showed that TBK1 could interact with the full-length OPTN and the OPTN(1–119) fragment, whereas deletion of either the C-terminal region of TBK1 or the N-terminal region of OPTN completely abolished the OPTN/TBK1 complex formation (Fig. 1b)
To further narrow down the TBK1-binding region in OPTN, we purified the recombinant proteins of two OPTN N-terminal fragments, OPTN(1–119) and OPTN(26–119), and used analytical gel filtration chromatography assay to analyse their interactions with TBK1 CTD
Summary
Optineurin is an important autophagy receptor involved in several selective autophagy processes, during which its function is regulated by TBK1. We determine the crystal structures of optineurin/TBK1 complex and the related NAP1/TBK1 complex, uncovering the detailed molecular mechanism governing the optineurin and TBK1 interaction, and revealing a general binding mode between TBK1 and its associated adaptor proteins. The detailed molecular mechanism governing the specific interactions between autophagy receptors and their regulatory proteins, as well as the mechanistic explanations to the identified disease-associated mutations are still elusive. The structures of OPTN NTD in complex with TBK1 CTD and the related NAP1/TBK1 complex solved in this study elucidate the detailed molecular mechanism underlying the OPTN and TBK1 interaction and uncover a general interaction mode governing TBK1’s binding to all of its currently identified binding adaptor proteins. Our findings are valuable for understanding the functions of OPTN and TBK1 in selective autophagy, as well as the pathogenesis of neurodegenerative diseases caused by mutations of OPTN and TBK1
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