Cleavage site selection within a folded substrate by the ATP-dependent Lon protease

Gabriela Ondrovičová, Tong Liu, Kamalendra Singh, Bin Tian, Hong Li, Oleksandr Gakh, Dušan Perečko, Jiří Janata, Zvi Granot, Joseph Orly, Eva Kutejová*, Carolyn K. Suzuki

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

94 Scopus citations


Mechanistic studies of ATP-dependent proteolysis demonstrate that substrate unfolding is a prerequisite for processive peptide bond hydrolysis. We show that mitochondrial Lon also degrades folded proteins and initiates substrate cleavage non-processively. Two mitochondrial substrates with known or homology-derived three-dimensional structures were used: the mitochondrial processing peptidase α-subunit (MPPα) and the steroidogenic acute regulatory protein (StAR). Peptides generated during a time course of Lon-mediated proteolysis were identified and mapped within the primary, secondary, and tertiary structure of the substrate. Initiating cleavages occurred preferentially between hydrophobic amino acids located within highly charged environments at the surface of the folded protein. Subsequent cleavages proceeded sequentially along the primary polypeptide sequence. We propose that Lon recognizes specific surface determinants or folds, initiates proteolysis at solvent-accessible sites, and generates unfolded polypeptides that are then processively degraded.

Original languageAmerican English
Pages (from-to)25103-25110
Number of pages8
JournalJournal of Biological Chemistry
Issue number26
StatePublished - 1 Jul 2005


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