Alzheimer's Aβ 1‐40 peptide degradation by thermolysin: evidence of inhibition by a C‐terminal Aβ product
Abstract
The interaction of the amyloid‐β peptide (Aβ) with thermolysin ( TLN ) was investigated by X‐ray crystallography. Structural models of the complexes of TLN with several Aβ fragments show that, despite the numerous possible cleavage sites of the Aβ sequence, the C‐terminal product of Ala30‐Ile31 cleavage does not dissociate, thus inhibiting the enzyme. The high similarity between the TLN structural motif and neprilysin ( NEP ), the most extensively studied peptidase associated with Aβ clearance, suggests that NEP should be more efficient against Aβ polymorphs where Ala30‐Ile31 is inaccessible, which is in agreement with studies in living mice that point to the limited role of NEP in degrading soluble Aβ and its higher ability to degrade insoluble and/or oligomeric Aβ forms, producing only the Aβ 10–37 intermediate.
- Authors:
-
- i3S – Instituto de Investigação e Inovação em Saúde Porto Portugal, IBMC – Instituto de Biologia Molecular e Celular Universidade do Porto Portugal, ICBAS – Instituto de Ciências Biomédicas Abel Salazar Porto Portugal
- Publication Date:
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1483142
- Resource Type:
- Publisher's Accepted Manuscript
- Journal Name:
- FEBS Letters
- Additional Journal Information:
- Journal Name: FEBS Letters Journal Volume: 593 Journal Issue: 1; Journal ID: ISSN 0014-5793
- Publisher:
- Wiley Blackwell (John Wiley & Sons)
- Country of Publication:
- Netherlands
- Language:
- English
Citation Formats
Leite, José P., and Gales, Luís. Alzheimer's Aβ 1‐40 peptide degradation by thermolysin: evidence of inhibition by a C‐terminal Aβ product. Netherlands: N. p., 2018.
Web. doi:10.1002/1873-3468.13285.
Leite, José P., & Gales, Luís. Alzheimer's Aβ 1‐40 peptide degradation by thermolysin: evidence of inhibition by a C‐terminal Aβ product. Netherlands. https://doi.org/10.1002/1873-3468.13285
Leite, José P., and Gales, Luís. Fri .
"Alzheimer's Aβ 1‐40 peptide degradation by thermolysin: evidence of inhibition by a C‐terminal Aβ product". Netherlands. https://doi.org/10.1002/1873-3468.13285.
@article{osti_1483142,
title = {Alzheimer's Aβ 1‐40 peptide degradation by thermolysin: evidence of inhibition by a C‐terminal Aβ product},
author = {Leite, José P. and Gales, Luís},
abstractNote = {The interaction of the amyloid‐β peptide (Aβ) with thermolysin ( TLN ) was investigated by X‐ray crystallography. Structural models of the complexes of TLN with several Aβ fragments show that, despite the numerous possible cleavage sites of the Aβ sequence, the C‐terminal product of Ala30‐Ile31 cleavage does not dissociate, thus inhibiting the enzyme. The high similarity between the TLN structural motif and neprilysin ( NEP ), the most extensively studied peptidase associated with Aβ clearance, suggests that NEP should be more efficient against Aβ polymorphs where Ala30‐Ile31 is inaccessible, which is in agreement with studies in living mice that point to the limited role of NEP in degrading soluble Aβ and its higher ability to degrade insoluble and/or oligomeric Aβ forms, producing only the Aβ 10–37 intermediate.},
doi = {10.1002/1873-3468.13285},
journal = {FEBS Letters},
number = 1,
volume = 593,
place = {Netherlands},
year = {Fri Nov 23 00:00:00 EST 2018},
month = {Fri Nov 23 00:00:00 EST 2018}
}
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