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Structural insights into the interaction and disease mechanism of neurodegenerative disease-associated optineurin and TBK1 proteins
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Structural insights into the interaction and disease mechanism of neurodegenerative disease-associated optineurin and TBK1 proteins
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Journal Article
Structural insights into the interaction and disease mechanism of neurodegenerative disease-associated optineurin and TBK1 proteins
2016
Overview
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.
Mutations in optineurin that cause defects in the interaction with TBK1 are associated with neurodegenerative diseases. Here, the authors report the structure of this complex, and outline a general binding mode for these proteins.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 82/16
/ 82/80
/ 82/83
/ Amyotrophic lateral sclerosis
/ Disease
/ Genetic Predisposition to Disease
/ Glaucoma
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Mutation
/ Neurodegenerative Diseases - genetics
/ Protein-Serine-Threonine Kinases - genetics
/ Protein-Serine-Threonine Kinases - metabolism
/ Proteins
/ Science
