title: Mitochondrial protein turnover: role of the precursor intermediate peptidase Oct1 in protein stabilization.
abstract: Most mitochondrial proteins are encoded in the nucleus as precursor proteins and carry N-terminal presequences for import into the organelle. The vast majority of presequences are proteolytically removed by the mitochondrial processing peptidase (MPP) localized in the matrix. A subset of precursors with a characteristic amino acid motif is additionally processed by the mitochondrial intermediate peptidase (MIP) octapeptidyl aminopeptidase 1 (Oct1), which removes an octapeptide from the N-terminus of the precursor intermediate. However, the function of this second cleavage step is elusive. In this paper, we report the identification of a novel Oct1 substrate protein with an unusual cleavage motif. Inspection of the Oct1 substrates revealed that the N-termini of the intermediates typically carry a destabilizing amino acid residue according to the N-end rule of protein degradation, whereas mature proteins carry stabilizing N-terminal residues. We compared the stability of intermediate and mature forms of Oct1 substrate proteins in organello and in vivo and found that Oct1 cleavage increases the half-life of its substrate proteins, most likely by removing destabilizing amino acids at the intermediate's N-terminus. Thus Oct1 converts unstable precursor intermediates generated by MPP into stable mature proteins.
authors.affiliation: Institut für Biochemie und Molekularbiologie, ZBMZ, Universität Freiburg, 79104 Freiburg, Germany.
authors.forename: F-Nora
authors.initials: FN
authors.lastname: Vögtle
authors.forename: Claudia
authors.initials: C
authors.lastname: Prinz
authors.forename: Josef
authors.initials: J
authors.lastname: Kellermann
authors.forename: Friedrich
authors.initials: F
authors.lastname: Lottspeich
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Pfanner
authors.forename: Chris
authors.initials: C
authors.lastname: Meisinger
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D006207:Half-Life; D008666:Metalloendopeptidases / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D015388:Organelles / Q000378:metabolism; D027702:Organic Cation Transporter 1 / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D000096122:Mitochondrial Processing Peptidase
chemical_list: D008666:Metalloendopeptidases; D024101:Mitochondrial Proteins; D027702:Organic Cation Transporter 1; D011498:Protein Precursors; D000096122:Mitochondrial Processing Peptidase; C068038:mitochondrial intermediate peptidase