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Insulin-degrading enzyme prevents α-synuclein fibril formation in a nonproteolytical manner.

Sandeep K Sharma ; Erik Chorell ; Pär Steneberg ; Emma Vernersson-Lindahl ; Helena Edlund ; Pernilla Wittung-Stafshede (Institutionen för biologi och bioteknik, Kemisk biologi)
Scientific reports (2045-2322). Vol. 5 (2015), p. 12531.
[Artikel, refereegranskad vetenskaplig]

The insulin-degrading enzyme (IDE) degrades amyloidogenic proteins such as Amyloid β (Αβ) and Islet Amyloid Polypeptide (IAPP), i.e. peptides associated with Alzheimer's disease and type 2 diabetes, respectively. In addition to the protease activity normally associated with IDE function an additional activity involving the formation of stable, irreversible complexes with both Αβ and α-synuclein, an amyloidogenic protein involved in Parkinson's disease, was recently proposed. Here, we have investigated the functional consequences of IDE-α-synuclein interactions in vitro. We demonstrate that IDE in a nonproteolytic manner and at sub-stoichiometric ratios efficiently inhibits α-synuclein fibril formation by binding to α-synuclein oligomers making them inert to amyloid formation. Moreover, we show that, within a defined range of α-synuclein concentrations, interaction with α-synuclein oligomers increases IDE's proteolytic activity on a fluorogenic substrate. We propose that the outcomes of IDE-α-synuclein interactions, i.e. protection against α-synuclein amyloid formation and stimulated IDE protease activity, may be protective in vivo.

Nyckelord: Amyloid, chemistry, Calorimetry, methods, Insulysin, chemistry, Microscopy, Atomic Force, Protein Multimerization, Thiazoles, chemistry, alpha-Synuclein, chemistry

Denna post skapades 2016-12-22. Senast ändrad 2017-10-03.
CPL Pubid: 246465


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