title: Structure of the catalytic domain of the human mitochondrial Lon protease: proposed relation of oligomer formation and activity.
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 A 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 3(10) helix attached to the N-terminal end of alpha-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.
authors.affiliation: York Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5YW, United Kingdom.
authors.forename: Javier
authors.initials: J
authors.lastname: García-Nafría
authors.forename: Gabriela
authors.initials: G
authors.lastname: Ondrovicová
authors.forename: Elena
authors.initials: E
authors.lastname: Blagova
authors.forename: Vladimir M
authors.initials: VM
authors.lastname: Levdikov
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Bauer
authors.forename: Carolyn K
authors.initials: CK
authors.lastname: Suzuki
authors.forename: Eva
authors.initials: E
authors.lastname: Kutejová
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Wilkinson
authors.forename: Keith S
authors.initials: KS
authors.lastname: Wilson
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D049070:Protease La / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D055503:Protein Multimerization; D021122:Protein Subunits; D016415:Sequence Alignment
chemical_list: D021122:Protein Subunits; D049070:Protease La