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Structure and assembly mechanisms of toxic human islet amyloid polypeptide oligomers associated with copper
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 invest...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Royal Society of Chemistry
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020819/ https://www.ncbi.nlm.nih.gov/pubmed/30155193 http://dx.doi.org/10.1039/c6sc00153j |
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author | Lee, Shin Jung C. Choi, Tae Su Lee, Jong Wha Lee, Hyuck Jin Mun, Dong-Gi Akashi, Satoko Lee, Sang-Won Lim, Mi Hee Kim, Hugh I. |
author_facet | Lee, Shin Jung C. Choi, Tae Su Lee, Jong Wha Lee, Hyuck Jin Mun, Dong-Gi Akashi, Satoko Lee, Sang-Won Lim, Mi Hee Kim, Hugh I. |
author_sort | Lee, Shin Jung C. |
collection | PubMed |
description | 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 (R(g) ∼ 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 toxic to pancreatic β-cells. On the other hand, metal-free hIAPP and Zn(ii)-associated hIAPP monomers generate relatively less toxic aggregates that eventually grow into fibrils. We suggest that the coordination of hIAPP to Cu(ii) and the relatively high stability (K(a), ca. 10(8) M(–1)) of hIAPP–Cu(ii) complexes result in the abnormal conformation and toxicity of hIAPP oligomers. Overall, through combining multiple biophysical methods, our studies suggest that molecular interactions between hIAPP and Cu(ii) induce a different pathway for hIAPP assembly. This work will advance our knowledge of the conformational basis, assembly mechanism, and toxicity of small soluble amyloid oligomers. |
format | Online Article Text |
id | pubmed-6020819 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-60208192018-08-28 Structure and assembly mechanisms of toxic human islet amyloid polypeptide oligomers associated with copper Lee, Shin Jung C. Choi, Tae Su Lee, Jong Wha Lee, Hyuck Jin Mun, Dong-Gi Akashi, Satoko Lee, Sang-Won Lim, Mi Hee Kim, Hugh I. Chem Sci Chemistry 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 (R(g) ∼ 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 toxic to pancreatic β-cells. On the other hand, metal-free hIAPP and Zn(ii)-associated hIAPP monomers generate relatively less toxic aggregates that eventually grow into fibrils. We suggest that the coordination of hIAPP to Cu(ii) and the relatively high stability (K(a), ca. 10(8) M(–1)) of hIAPP–Cu(ii) complexes result in the abnormal conformation and toxicity of hIAPP oligomers. Overall, through combining multiple biophysical methods, our studies suggest that molecular interactions between hIAPP and Cu(ii) induce a different pathway for hIAPP assembly. This work will advance our knowledge of the conformational basis, assembly mechanism, and toxicity of small soluble amyloid oligomers. Royal Society of Chemistry 2016-08-01 2016-05-16 /pmc/articles/PMC6020819/ /pubmed/30155193 http://dx.doi.org/10.1039/c6sc00153j Text en This journal is © The Royal Society of Chemistry 2016 http://creativecommons.org/licenses/by/3.0/ This article is freely available. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence (CC BY 3.0) |
spellingShingle | Chemistry Lee, Shin Jung C. Choi, Tae Su Lee, Jong Wha Lee, Hyuck Jin Mun, Dong-Gi Akashi, Satoko Lee, Sang-Won Lim, Mi Hee Kim, Hugh I. Structure and assembly mechanisms of toxic human islet amyloid polypeptide oligomers associated with copper |
title | Structure and assembly mechanisms of toxic human islet amyloid polypeptide oligomers associated with copper
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title_full | Structure and assembly mechanisms of toxic human islet amyloid polypeptide oligomers associated with copper
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title_fullStr | Structure and assembly mechanisms of toxic human islet amyloid polypeptide oligomers associated with copper
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title_full_unstemmed | Structure and assembly mechanisms of toxic human islet amyloid polypeptide oligomers associated with copper
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title_short | Structure and assembly mechanisms of toxic human islet amyloid polypeptide oligomers associated with copper
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title_sort | structure and assembly mechanisms of toxic human islet amyloid polypeptide oligomers associated with copper |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020819/ https://www.ncbi.nlm.nih.gov/pubmed/30155193 http://dx.doi.org/10.1039/c6sc00153j |
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