Alzheimer's Aβ 1‐40 peptide degradation by thermolysin: evidence of inhibition by a C‐terminal Aβ product

Leite, José P.; Gales, Luís

doi:10.1002/1873-3468.13285

Title: Alzheimer's Aβ _1‐40 peptide degradation by thermolysin: evidence of inhibition by a C‐terminal Aβ product

Journal Article · 22 November 2018 · FEBS Letters

DOI: https://doi.org/10.1002/1873-3468.13285 · OSTI ID:1483142

Leite, José P. ^[1]; Gales, Luís ^[1]

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

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.

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Sponsoring Organization:: USDOE

OSTI ID:: 1483142

Journal Information:: FEBS Letters, Journal Name: FEBS Letters Journal Issue: 1 Vol. 593; ISSN 0014-5793

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: Netherlands

Language:: English

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Title: Alzheimer's Aβ _1‐40 peptide degradation by thermolysin: evidence of inhibition by a C‐terminal Aβ product