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Structure of the catalytic domain of the human mitochondrial Lon protease: Proposed relation of oligomer formation and activity

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JournalProtein Science
DatePublished - May 2010
Issue number5
Volume19
Number of pages13
Pages (from-to)987-999
Original languageEnglish

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 angstrom 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. coil 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. coil 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. coil hexamer.

    Research areas

  • ATP-dependent protease, Lon protease, catalytic dyad, mitochondria, oligomerization and activity, ATP-DEPENDENT PROTEASE, N-TERMINAL DOMAIN, SER-LYS DYAD, CRYSTAL-STRUCTURE, ESCHERICHIA-COLI, PROTEOLYTIC DOMAIN, MOLECULAR-GRAPHICS, SELF-CLEAVAGE, LA LON, DNA

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