Molecular insights into substrate recognition and discrimination by the N-terminal domain of Lon AAA+ protease

eLife

Yi-Ting Kuo¹  Shiou-Ru Tzeng¹  Chia-Ying Hsu¹  Yin-Chu Tseng¹  Chien-Chu Lin²  Chung-I Chang³  Shing-Jong Huang⁴ 

[1] Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan;Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan;Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan;Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan;Instrumentation Center, National Taiwan University, Taipei, Taiwan;

关键词: Lon AAA+ protease;    N-terminal domain;    degrons;    misfolded proteins;    protein aggregates;    Meiothermus taiwanensis;    Other;   

DOI  :  10.7554/eLife.64056

来源: eLife Sciences Publications, Ltd

【 摘 要 】

The Lon AAA+ protease (LonA) is a ubiquitous ATP-dependent proteolytic machine, which selectively degrades damaged proteins or native proteins carrying exposed motifs (degrons). Here we characterize the structural basis for substrate recognition and discrimination by the N-terminal domain (NTD) of LonA. The results reveal that the six NTDs are attached to the hexameric LonA chamber by flexible linkers such that the formers tumble independently of the latter. Further spectral analyses show that the NTD selectively interacts with unfolded proteins, protein aggregates, and degron-tagged proteins by two hydrophobic patches of its N-lobe, but not intrinsically disordered substrate, α-casein. Moreover, the NTD selectively binds to protein substrates when they are thermally induced to adopt unfolded conformations. Collectively, our findings demonstrate that NTDs enable LonA to perform protein quality control to selectively degrade proteins in damaged states and suggest that substrate discrimination and selective degradation by LonA are mediated by multiple NTD interactions.

【 授权许可】

CC BY