Structure of the catalytic domain of the human mitochondrial Lon protease: Proposed relation of oligomer formation and activity |
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Authors: | Javier García‐Nafría Gabriela Ondrovi?ová Elena Blagova Vladimir M Levdikov Jacob A Bauer Carolyn K Suzuki Eva Kutejová Anthony J Wilkinson Keith S Wilson |
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Institution: | 1. York Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5YW, United Kingdom;2. Institute of Molecular Biology, Department of Biochemistry, Slovak Academy of Sciences, Dúbravská cesta 21, 845 51 Bratislava, Slovakia;3. Department of Biochemistry and Molecular Biology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103;4. Institute of Microbiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic |
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Abstract: | ATP‐dependent proteases are crucial for cellular homeostasis. By degrading short‐lived regulatory proteins, they play an important role in the control of many cellular pathways and, through the degradation of abnormally misfolded proteins, protect the cell from a buildup of aggregates. Disruption or disregulation of mammalian mitochondrial Lon protease leads to severe changes in the cell, linked with carcinogenesis, apoptosis, and necrosis. Here we present the structure of the proteolytic domain of human mitochondrial Lon at 2 Å resolution. The fold resembles those of the three previously determined Lon proteolytic domains from Escherichia coli, Methanococcus jannaschii, and Archaeoglobus fulgidus. There are six protomers in the asymmetric unit, four arranged as two dimers. The intersubunit interactions within the two dimers are similar to those between adjacent subunits of the hexameric ring of E. coli Lon, suggesting that the human Lon proteolytic domain also forms hexamers. The active site contains a 310 helix attached to the N‐terminal end of α‐helix 2, which leads to the insertion of Asp852 into the active site, as seen in M. jannaschii. Structural considerations make it likely that this conformation is proteolytically inactive. When comparing the intersubunit interactions of human with those of E. coli Lon taken with biochemical data leads us to propose a mechanism relating the formation of Lon oligomers with a conformational shift in the active site region coupled to a movement of a loop in the oligomer interface, converting the proteolytically inactive form seen here to the active one in the E. coli hexamer. |
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Keywords: | ATP‐dependent protease Lon protease catalytic dyad mitochondria oligomerization and activity |
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