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

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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; Gräslund, Astrid; Lehtiö, Janne; Stenmark, Pål; Glaser, Elzbieta.

I: Journal of Molecular Biology, Vol. 430, Nr. 3, 02.02.2018, s. 348-362.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

Teixeira, PF, Masuyer, G, Pinho, CM, Branca, RMM, Kmiec, B, Wallin, C, Wärmländer, SKTS, Berntsson, RP-A, Ankarcrona, M, Gräslund, A, Lehtiö, J, Stenmark, P & Glaser, E 2018, 'Mechanism of Peptide Binding and Cleavage by the Human Mitochondrial Peptidase Neurolysin', Journal of Molecular Biology, vol. 430, nr. 3, s. 348-362. https://doi.org/10.1016/j.jmb.2017.11.011

APA

Teixeira, P. F., Masuyer, G., Pinho, C. M., Branca, R. M. M., Kmiec, B., Wallin, C., ... Glaser, E. (2018). 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

CBE

Teixeira PF, Masuyer G, Pinho CM, Branca RMM, Kmiec B, Wallin C, Wärmländer SKTS, Berntsson RP-A, Ankarcrona M, Gräslund A, Lehtiö J, Stenmark P, Glaser E. 2018. 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

MLA

Vancouver

Author

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 ; Gräslund, Astrid ; Lehtiö, Janne ; Stenmark, Pål ; Glaser, Elzbieta. / Mechanism of Peptide Binding and Cleavage by the Human Mitochondrial Peptidase Neurolysin. I: Journal of Molecular Biology. 2018 ; Vol. 430, Nr. 3. s. 348-362.

RIS

TY - JOUR

T1 - Mechanism of Peptide Binding and Cleavage by the Human Mitochondrial Peptidase Neurolysin

AU - Teixeira, Pedro F

AU - Masuyer, Geoffrey

AU - Pinho, Catarina M

AU - Branca, Rui M M

AU - Kmiec, Beata

AU - Wallin, Cecilia

AU - Wärmländer, Sebastian K T S

AU - Berntsson, Ronnie P-A

AU - Ankarcrona, Maria

AU - Gräslund, Astrid

AU - Lehtiö, Janne

AU - Stenmark, Pål

AU - Glaser, Elzbieta

N1 - Copyright © 2017 Elsevier Ltd. All rights reserved.

PY - 2018/2/2

Y1 - 2018/2/2

N2 - 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.

AB - 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.

KW - Amino Acid Sequence

KW - Amyloid beta-Peptides/chemistry

KW - Animals

KW - Crystallography, X-Ray

KW - HeLa Cells

KW - Humans

KW - Metalloendopeptidases/chemistry

KW - Mice, Inbred C57BL

KW - Mitochondria/metabolism

KW - Models, Molecular

KW - Neurotensin/chemistry

KW - Peptides/chemistry

KW - Protein Binding

KW - Protein Conformation

KW - Proteolysis

KW - Substrate Specificity

U2 - 10.1016/j.jmb.2017.11.011

DO - 10.1016/j.jmb.2017.11.011

M3 - Article

VL - 430

SP - 348

EP - 362

JO - Journal of Molecular Biology

JF - Journal of Molecular Biology

SN - 1089-8638

IS - 3

ER -