Structure and assembly mechanisms of toxic human islet amyloid polypeptide oligomers associated with copper

Chemical Science
Shin Jung C LeeHugh I Kim

Abstract

Amyloidosis is a clinical disorder implicated with the formation of toxic amyloid aggregates. Despite their pathological significance, it is challenging to define the structural characteristics of amyloid oligomers owing to their metastable nature. Herein, we report structural and mechanistic investigations of human islet amyloid polypeptide (hIAPP) oligomers, found in type II diabetes mellitus, in both the absence and presence of disease-relevant metal ions [i.e., Cu(ii) and Zn(ii)]. These metal ions show suppressive effects on hIAPP fibrillation and facilitate the generation of toxic oligomers. Using circular dichroism spectroscopy, transmission electron microscopy, gel electrophoresis, small-angle X-ray scattering, and ion mobility-mass spectrometry, we investigated the assembly mechanisms of hIAPP oligomers in the presence and absence of metal ions. Oligomerization of both metal-free hIAPP and metal-associated hIAPP monomers is initiated following a similar growth model. However, in the presence of Cu(ii), hIAPP monomers self-assemble into small globular aggregates (Rg ∼ 45 Å) with a random coil structure. This Cu(ii)-associated hIAPP oligomer shows an off-pathway aggregation, and is suggested to be an end product which is ...Continue Reading

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Citations

Aug 13, 2017·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Weihong DuJufei Xu
Oct 18, 2019·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Ishita PalSomdatta Ghosh Dey
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Sep 1, 2021·Journal of the American Society for Mass Spectrometry·Chae Eun HeoHugh I Kim
Jan 26, 2022·Journal of the American Chemical Society·Dongjoon ImJeong-Mo Choi

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Methods Mentioned

BETA
circular
transmission
electrophoresis
X-ray
electron capture dissociation

Software Mentioned

GNOM

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