Mechanism of Peptide Binding and Cleavage by the Human Mitochondrial Peptidase Neurolysin |
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Authors: | 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 |
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Affiliation: | 1. Department of Biochemistry and Biophysics, Stockholm University, Arrhenius Laboratories for Natural Sciences, Stockholm, Sweden;2. Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Science and Society, Karolinska Institutet, Stockholm, Sweden;3. Clinical Proteomics Mass Spectrometry, Department of Oncology-Pathology, Science for Life Laboratory and Karolinska Institutet, Stockholm, Sweden |
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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 hNLNE475Q 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. |
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Keywords: | mitochondria proteolysis peptide degradation peptidase presequence MPP mitochondrial processing peptidase PreP presequence protease OOP organellar oligopeptidase Aβ amyloid-β peptide hNLN human mitochondrial peptidase neurolysin NT neurotensin CD circular dichroism PBS phosphate-buffered saline |
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