Catalytic cycling of human mitochondrial Lon protease

Mohammed, Inayathulla and Schmitz, Kai A. and Schenck, Niko and Balasopoulos, Dimitrios and Topitsch, Annika and Maier, Timm and Abrahams, Jan Pieter. (2022) Catalytic cycling of human mitochondrial Lon protease. Structure, 30 (9). pp. 1254-1268.e7.

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Official URL: https://edoc.unibas.ch/89769/

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The mitochondrial Lon protease (LonP1) regulates mitochondrial health by removing redundant proteins from the mitochondrial matrix. We determined LonP1 in eight nucleotide-dependent conformational states by cryoelectron microscopy (cryo-EM). The flexible assembly of N-terminal domains had 3-fold symmetry, and its orientation depended on the conformational state. We show that a conserved structural motif around T803 with a high similarity to the trypsin catalytic triad is essential for proteolysis. We show that LonP1 is not regulated by redox potential, despite the presence of two conserved cysteines at disulfide-bonding distance in its unfoldase core. Our data indicate how sequential ATP hydrolysis controls substrate protein translocation in a 6-fold binding change mechanism. Substrate protein translocation, rather than ATP hydrolysis, is a rate-limiting step, suggesting that LonP1 is a Brownian ratchet with ATP hydrolysis preventing translocation reversal. 3-fold rocking motions of the flexible N-domain assembly may assist thermal unfolding of the substrate protein.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Maier)
05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Nano-diffraction of Biological Specimen (Abrahams)
UniBasel Contributors:Maier, Timm and Abrahams, Jan Pieter and Topitsch, Annika and Balasopoulos, Dimitrios and Schenck, Niko
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Cell Press
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:23 Feb 2023 15:39
Deposited On:27 Sep 2022 09:24

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