Amyloid Self-Assembly of hIAPP8-20 via the Accumulation of Helical Oligomers, α-Helix to β-Sheet Transition, and Formation of β-Barrel Intermediates

Yunxiang Sun, Aleksandr Kakinen, Yanting Xing, Pouya Faridi, Aparna Nandakumar, Anthony W. Purcell, Thomas P. Davis, Pu Chun Ke, Feng Ding

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The self-assembly of human islet amyloid polypeptide (hIAPP) into β-sheet-rich nanofibrils is associated with the pathogeny of type 2 diabetes. Soluble hIAPP is intrinsically disordered with N-terminal residues 8–17 as α-helices. To understand the contribution of the N-terminal helix to the aggregation of full-length hIAPP, here the oligomerization dynamics of the hIAPP fragment 8–20 (hIAPP8-20) are investigated with combined computational and experimental approaches. hIAPP8-20 forms cross-β nanofibrils in silico from isolated helical monomers via the helical oligomers and α-helices to β-sheets transition, as confirmed by transmission electron microscopy, atomic force microscopy, circular dichroism spectroscopy, Fourier transform infrared spectroscopy, and reversed-phase high performance liquid chromatography. The computational results also suggest that the critical nucleus of aggregation corresponds to hexamers, consistent with a recent mass-spectroscopy study of hIAPP8-20 aggregation. hIAPP8-20 oligomers smaller than hexamers are helical and unstable, while the α-to-β transition starts from the hexamers. Converted β-sheet-rich oligomers first form β-barrel structures as intermediates before aggregating into cross-β nanofibrils. This study uncovers a complete picture of hIAPP8-20 peptide oligomerization, aggregation nucleation via conformational conversion, formation of β-barrel intermediates, and assembly of cross-β protofibrils, thereby shedding light on the aggregation of full-length hIAPP, a hallmark of pancreatic beta-cell degeneration.

Original languageEnglish
Article number1805166
Number of pages10
JournalSmall
DOIs
Publication statusAccepted/In press - 2019

Keywords

  • beta barrels
  • helical oligomers
  • helix-to-sheet transitions
  • human islet amyloid polypeptide

Cite this

@article{ef41760d769840be8579958ff0500c28,
title = "Amyloid Self-Assembly of hIAPP8-20 via the Accumulation of Helical Oligomers, α-Helix to β-Sheet Transition, and Formation of β-Barrel Intermediates",
abstract = "The self-assembly of human islet amyloid polypeptide (hIAPP) into β-sheet-rich nanofibrils is associated with the pathogeny of type 2 diabetes. Soluble hIAPP is intrinsically disordered with N-terminal residues 8–17 as α-helices. To understand the contribution of the N-terminal helix to the aggregation of full-length hIAPP, here the oligomerization dynamics of the hIAPP fragment 8–20 (hIAPP8-20) are investigated with combined computational and experimental approaches. hIAPP8-20 forms cross-β nanofibrils in silico from isolated helical monomers via the helical oligomers and α-helices to β-sheets transition, as confirmed by transmission electron microscopy, atomic force microscopy, circular dichroism spectroscopy, Fourier transform infrared spectroscopy, and reversed-phase high performance liquid chromatography. The computational results also suggest that the critical nucleus of aggregation corresponds to hexamers, consistent with a recent mass-spectroscopy study of hIAPP8-20 aggregation. hIAPP8-20 oligomers smaller than hexamers are helical and unstable, while the α-to-β transition starts from the hexamers. Converted β-sheet-rich oligomers first form β-barrel structures as intermediates before aggregating into cross-β nanofibrils. This study uncovers a complete picture of hIAPP8-20 peptide oligomerization, aggregation nucleation via conformational conversion, formation of β-barrel intermediates, and assembly of cross-β protofibrils, thereby shedding light on the aggregation of full-length hIAPP, a hallmark of pancreatic beta-cell degeneration.",
keywords = "beta barrels, helical oligomers, helix-to-sheet transitions, human islet amyloid polypeptide",
author = "Yunxiang Sun and Aleksandr Kakinen and Yanting Xing and Pouya Faridi and Aparna Nandakumar and Purcell, {Anthony W.} and Davis, {Thomas P.} and Ke, {Pu Chun} and Feng Ding",
year = "2019",
doi = "10.1002/smll.201805166",
language = "English",
journal = "Small",
issn = "1613-6810",
publisher = "Wiley-Blackwell",

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TY - JOUR

T1 - Amyloid Self-Assembly of hIAPP8-20 via the Accumulation of Helical Oligomers, α-Helix to β-Sheet Transition, and Formation of β-Barrel Intermediates

AU - Sun, Yunxiang

AU - Kakinen, Aleksandr

AU - Xing, Yanting

AU - Faridi, Pouya

AU - Nandakumar, Aparna

AU - Purcell, Anthony W.

AU - Davis, Thomas P.

AU - Ke, Pu Chun

AU - Ding, Feng

PY - 2019

Y1 - 2019

N2 - The self-assembly of human islet amyloid polypeptide (hIAPP) into β-sheet-rich nanofibrils is associated with the pathogeny of type 2 diabetes. Soluble hIAPP is intrinsically disordered with N-terminal residues 8–17 as α-helices. To understand the contribution of the N-terminal helix to the aggregation of full-length hIAPP, here the oligomerization dynamics of the hIAPP fragment 8–20 (hIAPP8-20) are investigated with combined computational and experimental approaches. hIAPP8-20 forms cross-β nanofibrils in silico from isolated helical monomers via the helical oligomers and α-helices to β-sheets transition, as confirmed by transmission electron microscopy, atomic force microscopy, circular dichroism spectroscopy, Fourier transform infrared spectroscopy, and reversed-phase high performance liquid chromatography. The computational results also suggest that the critical nucleus of aggregation corresponds to hexamers, consistent with a recent mass-spectroscopy study of hIAPP8-20 aggregation. hIAPP8-20 oligomers smaller than hexamers are helical and unstable, while the α-to-β transition starts from the hexamers. Converted β-sheet-rich oligomers first form β-barrel structures as intermediates before aggregating into cross-β nanofibrils. This study uncovers a complete picture of hIAPP8-20 peptide oligomerization, aggregation nucleation via conformational conversion, formation of β-barrel intermediates, and assembly of cross-β protofibrils, thereby shedding light on the aggregation of full-length hIAPP, a hallmark of pancreatic beta-cell degeneration.

AB - The self-assembly of human islet amyloid polypeptide (hIAPP) into β-sheet-rich nanofibrils is associated with the pathogeny of type 2 diabetes. Soluble hIAPP is intrinsically disordered with N-terminal residues 8–17 as α-helices. To understand the contribution of the N-terminal helix to the aggregation of full-length hIAPP, here the oligomerization dynamics of the hIAPP fragment 8–20 (hIAPP8-20) are investigated with combined computational and experimental approaches. hIAPP8-20 forms cross-β nanofibrils in silico from isolated helical monomers via the helical oligomers and α-helices to β-sheets transition, as confirmed by transmission electron microscopy, atomic force microscopy, circular dichroism spectroscopy, Fourier transform infrared spectroscopy, and reversed-phase high performance liquid chromatography. The computational results also suggest that the critical nucleus of aggregation corresponds to hexamers, consistent with a recent mass-spectroscopy study of hIAPP8-20 aggregation. hIAPP8-20 oligomers smaller than hexamers are helical and unstable, while the α-to-β transition starts from the hexamers. Converted β-sheet-rich oligomers first form β-barrel structures as intermediates before aggregating into cross-β nanofibrils. This study uncovers a complete picture of hIAPP8-20 peptide oligomerization, aggregation nucleation via conformational conversion, formation of β-barrel intermediates, and assembly of cross-β protofibrils, thereby shedding light on the aggregation of full-length hIAPP, a hallmark of pancreatic beta-cell degeneration.

KW - beta barrels

KW - helical oligomers

KW - helix-to-sheet transitions

KW - human islet amyloid polypeptide

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U2 - 10.1002/smll.201805166

DO - 10.1002/smll.201805166

M3 - Article

JO - Small

JF - Small

SN - 1613-6810

M1 - 1805166

ER -