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

Shin Jung C. Lee, Tae Su Choi, Jong Wha Lee, Hyuck Jin Lee, Dong Gi Mun, Satoko Akashi, Sang Won Lee, Mi Hee Lim, Hugh I. Kim

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36 Citations (Scopus)


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 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 (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.

Original languageEnglish
Pages (from-to)5398-5406
Number of pages9
JournalChemical Science
Issue number8
Publication statusPublished - 2016

Bibliographical note

Funding Information:
This work was supported by funding from the Basic Science Research (Grant No. NRF-2013R1A1A2008974) through the National Research Foundation (NRF) of Korea funded by the Ministry of Science, ICT, and Future Planning, Basic Science Research Program (Grant No. 2010-0020209) through the NRF funded by the Ministry of Education, and the Korea Health Technology R&D Project (Grant No. HT13C-0011-040013) through the Korea Health Industry Development Institute (to H. I. K.); grants from the NRF of Korea (NRF-2014S1A2A2028270 and NRF-2014R1A2A2A01004877) (to M. H. L.); a grant from the Ministry of Science, ICT, and Future Planning, Republic of Korea (Grant No. NRF-2014M3C7A1046047) (to S.-W. L.). The synchrotron X-ray scattering measurements at the Pohang Accelerator Laboratory were supported by the Ministry of Education and Science Technology. S. J. C. L. was supported by an NRF grant funded by the Korean Government (NRF-2011-Global Ph.D. Fellowship Program). T. S. C. acknowledges support from a TJ Park Fellowship.

Publisher Copyright:
© 2016 The Royal Society of Chemistry.

ASJC Scopus subject areas

  • General Chemistry


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