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Mechanism of Peptide Binding and Cleavage by the Human Mitochondrial Peptidase Neurolysin
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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Number of Authors: 132018 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 430, no 3, p. 348-362Article in journal (Refereed) Published
Abstract [en]

Proteolysis plays an important role in mitochondria! 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 angstrom 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-beta peptide, A beta 1-40, associated with Alzheimer disease, particularly cleaving the hydrophobic fragment A beta 35-40. These findings suggest that a network of proteases may be required for complete degradation of peptides localized in mitochondria.

Place, publisher, year, edition, pages
2018. Vol. 430, no 3, p. 348-362
Keywords [en]
mitochondria, proteolysis, peptide degradation, peptidase, presequence
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:su:diva-153622DOI: 10.1016/j.jmb.2017.11.011ISI: 000424961400009PubMedID: 29183787OAI: oai:DiVA.org:su-153622DiVA, id: diva2:1189984
Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-03-13Bibliographically approved

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Teixeira, Pedro F.Masuyer, GeoffreyKmiec, BeataWallin, CeciliaWärmländer, Sebastian K. T. S.Gräslund, AstridStenmark, PålGlaser, Elzbieta
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