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

Teixeira, Pedro F ; Masuyer, Geoffrey ; Pinho, Catarina M ; Branca, Rui M M ; Kmiec, Beata ; Wallin, Cecilia ; Wärmländer, Sebastian K T S ; Berntsson, Ronnie P-A ; Ankarcrona, Maria and Gräslund, Astrid , et al. (2018) In Journal of Molecular Biology 430(3). p.348-362
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 2.7Å revealed a closed conformation with an internal cavity that restricts... (More)

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 2.7Å 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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publishing date
type
Contribution to journal
publication status
published
keywords
Amino Acid Sequence, Amyloid beta-Peptides/chemistry, Animals, Crystallography, X-Ray, HeLa Cells, Humans, Metalloendopeptidases/chemistry, Mice, Inbred C57BL, Mitochondria/metabolism, Models, Molecular, Neurotensin/chemistry, Peptides/chemistry, Protein Binding, Protein Conformation, Proteolysis, Substrate Specificity
in
Journal of Molecular Biology
volume
430
issue
3
pages
348 - 362
publisher
Elsevier
external identifiers
  • pmid:29183787
  • scopus:85039447386
ISSN
1089-8638
DOI
10.1016/j.jmb.2017.11.011
language
English
LU publication?
no
additional info
Copyright © 2017 Elsevier Ltd. All rights reserved.
id
3805d11c-2777-4f52-ba90-fd13f203cf15
date added to LUP
2019-04-30 07:51:51
date last changed
2024-03-19 05:43:59
@article{3805d11c-2777-4f52-ba90-fd13f203cf15,
  abstract     = {{<p>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 2.7Å 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.</p>}},
  author       = {{Teixeira, Pedro F and Masuyer, Geoffrey and Pinho, Catarina M and Branca, Rui M M and Kmiec, Beata and Wallin, Cecilia and Wärmländer, Sebastian K T S and Berntsson, Ronnie P-A and Ankarcrona, Maria and Gräslund, Astrid and Lehtiö, Janne and Stenmark, Pål and Glaser, Elzbieta}},
  issn         = {{1089-8638}},
  keywords     = {{Amino Acid Sequence; Amyloid beta-Peptides/chemistry; Animals; Crystallography, X-Ray; HeLa Cells; Humans; Metalloendopeptidases/chemistry; Mice, Inbred C57BL; Mitochondria/metabolism; Models, Molecular; Neurotensin/chemistry; Peptides/chemistry; Protein Binding; Protein Conformation; Proteolysis; Substrate Specificity}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{3}},
  pages        = {{348--362}},
  publisher    = {{Elsevier}},
  series       = {{Journal of Molecular Biology}},
  title        = {{Mechanism of Peptide Binding and Cleavage by the Human Mitochondrial Peptidase Neurolysin}},
  url          = {{http://dx.doi.org/10.1016/j.jmb.2017.11.011}},
  doi          = {{10.1016/j.jmb.2017.11.011}},
  volume       = {{430}},
  year         = {{2018}},
}