Mechanism of Peptide Binding and Cleavage by the Human Mitochondrial Peptidase Neurolysin

Pedro F. Teixeira, Geoffrey Masuyer, Catarina M. Pinho, Rui M.M. Branca, Beata Kmiec, Cecilia Wallin, Sebastian K.T.S. Wärmländer, Ronnie P.A. Berntsson, Maria Ankarcrona, Astrid Gräslund, Janne Lehtiö, Pål Stenmark, Elzbieta Glaser

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Proteolysis plays an important role in mitochondrial biogenesis, from the processing of newly imported precursor proteins to the degradation of mitochondrial targeting peptides. Disruption of peptide degradation activity in yeast, plant and mammalian mitochondria is known to have deleterious consequences for organism physiology, highlighting the important role of mitochondrial peptidases. In the present work, we show that the human mitochondrial peptidase neurolysin (hNLN) can degrade mitochondrial presequence peptides as well as other fragments up to 19 amino acids long. The crystal structure of hNLN E475Q in complex with the products of neurotensin cleavage at 2.7 Å revealed a closed conformation with an internal cavity that restricts substrate length and highlighted the mechanism of enzyme opening/closing that is necessary for substrate binding and catalytic activity. Analysis of peptide degradation in vitro showed that hNLN cooperates with presequence protease (PreP or PITRM1) in the degradation of long targeting peptides and amyloid-β peptide, Aβ1–40, associated with Alzheimer disease, particularly cleaving the hydrophobic fragment Aβ35–40. These findings suggest that a network of proteases may be required for complete degradation of peptides localized in mitochondria.

Original languageEnglish
Pages (from-to)348-362
Number of pages15
JournalJournal of Molecular Biology
Volume430
Issue number3
Early online date26 Nov 2017
DOIs
Publication statusE-pub ahead of print - 26 Nov 2017

Keywords

  • mitochondria
  • peptidase
  • peptide degradation
  • presequence
  • proteolysis

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Teixeira, P. F., Masuyer, G., Pinho, C. M., Branca, R. M. M., Kmiec, B., Wallin, C., ... Glaser, E. (2017). Mechanism of Peptide Binding and Cleavage by the Human Mitochondrial Peptidase Neurolysin. Journal of Molecular Biology, 430(3), 348-362. https://doi.org/10.1016/j.jmb.2017.11.011