Insulin-degrading enzyme prevents α-synuclein fibril formation in a nonproteolytical manner.
Artikel i vetenskaplig tidskrift, 2015

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.

Calorimetry

Amyloid

methods

chemistry

chemistry

Insulysin

chemistry

Thiazoles

chemistry

Microscopy

Atomic Force

alpha-Synuclein

Protein Multimerization

Författare

Sandeep K Sharma

E. Chorell

Pär Steneberg

Emma Vernersson-Lindahl

Helena Edlund

Pernilla Wittung Stafshede

Chalmers, Biologi och bioteknik, Kemisk biologi

Scientific Reports

2045-2322 (ISSN)

Vol. 5 12531-

Ämneskategorier

Biokemi och molekylärbiologi

Biologiska vetenskaper

Biofysik

DOI

10.1038/srep12531

PubMed

26228656

Mer information

Skapat

2017-10-07