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

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 toxic to pancreatic ?-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 (Ka, ca. 108 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.

SUBMITTER: Lee SJC

PROVIDER: S-EPMC6020819 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

Lee Shin Jung C SJC Choi Tae Su TS Lee Jong Wha JW Lee Hyuck Jin HJ Mun Dong-Gi DG Akashi Satoko S Lee Sang-Won SW Lim Mi Hee MH Kim Hugh I HI

Chemical science 20160516 8

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>i.e.</i>, Cu(ii) and Zn(ii)]. The ...[more]

PMID: 30155193

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Project description:The accumulation of human islet amyloid polypeptide (hIAPP) on the surface of pancreatic β cells is closely related to the death of the cells. Divalent metal ions play a significant role in the cytotoxicity of hIAPP. In this study, we examined the roles played by the divalent metal ions of zinc, copper and calcium in the aggregation of both hIAPP18-27 fragment and full-length hIAPP and the ability of their oligomers to damage the membrane of POPC/POPG 4 : 1 LUVs using the ThT fluorescence, TEM, AFM, CD, ANS binding fluorescence and dye leakage experiments. We prepared metal-free and metal-associated oligomers that are similar in size and aggregate slowly using the short peptide and confirmed that the ability of the peptide oligomers to damage the lipid membrane is reduced by the binding to the metal ions, which is closely linked to the reducing hydrophobic exposure of the metal-associated oligomers. The study on the full-length hIAPP showed that the observed membrane damage induced by hIAPP oligomers is either mitigated at a peptide-to-metal ratio of 1 : 0.33 or aggravated at a peptide-to-metal ratio of 1 : 1 in the presence of Zn(ii) and Cu(ii), while the surface hydrophobicity of hIAPP oligomers was reduced at both peptide-to-metal ratios. The observed results of the membrane damage were attributed to the counteraction between a decrease in the disruptive ability of metal-associated oligomer species and an increase in the quantity of oligomers promoted by the binding of the metal ions to hIAPP oligomers. The former could play a predominant role in reducing the membrane damage at a peptide-to-metal ratio of 1 : 0.33, while the latter could play a predominant role in enhancing the membrane damage at a peptide-to-metal ratio of 1 : 1. This study shows that an enhanced membrane damage could be caused by the oligomer species with a decreased instead of an increased disruptive ability, given that the abundance of the oligomer species is high enough.

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

Publications

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

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