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Title: Sequence-Dependent Self-Assembly and Structural Diversity of Islet Amyloid Polypeptide-Derived β-Sheet Fibrils

Abstract

Determining the structural origins of amyloid fibrillation is essential for understanding both the pathology of amyloidosis and the rational design of inhibitors to prevent or reverse amyloid formation. In this work, the decisive roles of peptide structures on amyloid self-assembly and morphological diversity were investigated by the design of eight amyloidogenic peptides derived from islet amyloid polypeptide. Among the segments, two distinct morphologies were highlighted in the form of twisted and planar (untwisted) ribbons with varied diameters, thicknesses, and lengths. In particular, transformation of amyloid fibrils from twisted ribbons into untwisted structures was triggered by substitution of the C-terminal serine with threonine, where the side chain methyl group was responsible for the distinct morphological change. This effect was confirmed following serine substitution with alanine and valine and was ascribed to the restriction of intersheet torsional strain through the increased hydrophobic interactions and hydrogen bonding. We also studied the variation of fibril morphology (i.e., association and helicity) and peptide aggregation propensity by increasing the hydrophobicity of the peptide side group, capping the N-terminus, and extending sequence length. Lastly, we anticipate that our insights into sequence-dependent fibrillation and morphological diversity will shed light on the structural interpretation of amyloidogenesis and development ofmore » structure-specific imaging agents and aggregation inhibitors.« less

Authors:
 [1];  [1];  [2]; ORCiD logo [1]; ORCiD logo [2];  [1]; ORCiD logo [1];  [1];  [2];  [1];  [3];  [2];  [2]; ORCiD logo [2]; ORCiD logo [1]
  1. Imperial College, London (United Kingdom). Inst. of Biomedical Engineering, Dept. of Materials and Dept. of Bioengineering
  2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Foundry
  3. Imperial College, London (United Kingdom). Dept. of Life Sciences
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); Taiwan Strategic Alliance; Engineering and Physical Sciences Research Council (EPSRC)
OSTI Identifier:
1416928
Grant/Contract Number:
AC02-05CH11231; EP/K020641/1
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
ACS Nano
Additional Journal Information:
Journal Volume: 11; Journal Issue: 9; Journal ID: ISSN 1936-0851
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; amyloid fibrils; helical nanostructures; islet amyloid polypeptide; nanoribbons; self-assembly

Citation Formats

Wang, Shih-Ting, Lin, Yiyang, Spencer, Ryan K., Thomas, Michael R., Nguyen, Andy I., Amdursky, Nadav, Pashuck, E. Thomas, Skaalure, Stacey C., Song, Cheng Yu, Parmar, Paresh A., Morgan, Rhodri M., Ercius, Peter, Aloni, Shaul, Zuckermann, Ronald N., and Stevens, Molly M. Sequence-Dependent Self-Assembly and Structural Diversity of Islet Amyloid Polypeptide-Derived β-Sheet Fibrils. United States: N. p., 2017. Web. doi:10.1021/acsnano.7b02325.
Wang, Shih-Ting, Lin, Yiyang, Spencer, Ryan K., Thomas, Michael R., Nguyen, Andy I., Amdursky, Nadav, Pashuck, E. Thomas, Skaalure, Stacey C., Song, Cheng Yu, Parmar, Paresh A., Morgan, Rhodri M., Ercius, Peter, Aloni, Shaul, Zuckermann, Ronald N., & Stevens, Molly M. Sequence-Dependent Self-Assembly and Structural Diversity of Islet Amyloid Polypeptide-Derived β-Sheet Fibrils. United States. doi:10.1021/acsnano.7b02325.
Wang, Shih-Ting, Lin, Yiyang, Spencer, Ryan K., Thomas, Michael R., Nguyen, Andy I., Amdursky, Nadav, Pashuck, E. Thomas, Skaalure, Stacey C., Song, Cheng Yu, Parmar, Paresh A., Morgan, Rhodri M., Ercius, Peter, Aloni, Shaul, Zuckermann, Ronald N., and Stevens, Molly M. 2017. "Sequence-Dependent Self-Assembly and Structural Diversity of Islet Amyloid Polypeptide-Derived β-Sheet Fibrils". United States. doi:10.1021/acsnano.7b02325. https://www.osti.gov/servlets/purl/1416928.
@article{osti_1416928,
title = {Sequence-Dependent Self-Assembly and Structural Diversity of Islet Amyloid Polypeptide-Derived β-Sheet Fibrils},
author = {Wang, Shih-Ting and Lin, Yiyang and Spencer, Ryan K. and Thomas, Michael R. and Nguyen, Andy I. and Amdursky, Nadav and Pashuck, E. Thomas and Skaalure, Stacey C. and Song, Cheng Yu and Parmar, Paresh A. and Morgan, Rhodri M. and Ercius, Peter and Aloni, Shaul and Zuckermann, Ronald N. and Stevens, Molly M.},
abstractNote = {Determining the structural origins of amyloid fibrillation is essential for understanding both the pathology of amyloidosis and the rational design of inhibitors to prevent or reverse amyloid formation. In this work, the decisive roles of peptide structures on amyloid self-assembly and morphological diversity were investigated by the design of eight amyloidogenic peptides derived from islet amyloid polypeptide. Among the segments, two distinct morphologies were highlighted in the form of twisted and planar (untwisted) ribbons with varied diameters, thicknesses, and lengths. In particular, transformation of amyloid fibrils from twisted ribbons into untwisted structures was triggered by substitution of the C-terminal serine with threonine, where the side chain methyl group was responsible for the distinct morphological change. This effect was confirmed following serine substitution with alanine and valine and was ascribed to the restriction of intersheet torsional strain through the increased hydrophobic interactions and hydrogen bonding. We also studied the variation of fibril morphology (i.e., association and helicity) and peptide aggregation propensity by increasing the hydrophobicity of the peptide side group, capping the N-terminus, and extending sequence length. Lastly, we anticipate that our insights into sequence-dependent fibrillation and morphological diversity will shed light on the structural interpretation of amyloidogenesis and development of structure-specific imaging agents and aggregation inhibitors.},
doi = {10.1021/acsnano.7b02325},
journal = {ACS Nano},
number = 9,
volume = 11,
place = {United States},
year = 2017,
month = 8
}

Journal Article:
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  • The human islet amyloid polypeptide (hIAPP) co-operates with insulin to maintain glycemic balance. It also constitutes the amyloid plaques that aggregate in the pancreas of type-II diabetic patients. We have performed extensive in silico investigations to analyse the structural landscape of monomeric hIAPP, which is presumed to be intrinsically disordered. For this, we construct from first principles a highly predictive energy function that describes a monomeric hIAPP observed in a nuclear magnetic resonance experiment, as a local energy minimum. We subject our theoretical model of hIAPP to repeated heating and cooling simulations, back and forth between a high temperature regimemore » where the conformation resembles a random walker and a low temperature limit where no thermal motions prevail. We find that the final low temperature conformations display a high level of degeneracy, in a manner which is fully in line with the presumed intrinsically disordered character of hIAPP. In particular, we identify an isolated family of α-helical conformations that might cause the transition to amyloidosis, by nucleation.« less
  • The formation and pathological deposition of amyloid fibrils are defining features of many acquired and inherited disorders, including primary or light-chain-associated amyloidosis, Alzheimer`s disease, and adult-onset diabetes. No pharmacological methods exist to block this process or to effect the removal of fibrils from tissue, and thus, little can be done to prevent organ failure and ultimate death that result from deposition of amyloid. Knowledge of the pathogenesis, treatment, or prevention of these presently incurable diseases is limited due to the relative paucity of information regarding the biophysical basis of amyloid formation. Antibody light chains of different amino acid sequence showmore » differential amyloid-forming tendencies and, as such, can provide insight into the structural organization of amyloid fibrils as well as into basic mechanisms of protein self-assembly. We have compared primary structures of 180 human monoclonal light chains and have identified particular residues and positions within the variable domain that differentiate amyloid-from nonamyloid-associated proteins. We propose a molecular model that accounts for amyloid formation by antibody light chains and might also have implications for other forms of amyloidosis. 24 refs., 2 figs., 1 tab.« less
  • Human islet amyloid polypeptide (IAPP or amylin) is a 37-residue hormone found as fibrillar deposits in pancreatic extracts of nearly all type II diabetics. Although the cellular toxicity of IAPP has been established, the structure of the fibrillar form found in these deposits is unknown. Here we have crystallized two segments from IAPP, which themselves form amyloid-like fibrils. The atomic structures of these two segments, NNFGAIL and SSTNVG, were determined, and form the basis of a model for the most commonly observed, full-length IAPP polymorph.
  • The authors have cloned and sequenced a human islet amyloid polypeptide (IAPP) cDNA. A secretory 89 amino acid IAPP protein precursor is predicted from which the 37 amino acid IAPP molecule is formed by amino- and carboxyterminal proteolytic processing. The IAPP peptide is 43-46% identical in amino acid sequence to the two members of the calcitonin gene-related peptide (CGRP) family. Evolutionary conserved proteolytic processing sites indicate that similar proteases are involved in the maturation of IAPP and CGRP and that the IAPP amyloid polypeptide is identical to the normal proteolytic product of the IAPP precursor. A synthetic peptide corresponding tomore » a carboxyterminal fragment of human IAPP is shown to spontaneously form amyloid-like fibrils in vitro. Antibodies against this peptide cross-react with IAPP from species that develop amyloid in pancreatic islets in conjunction with age-related diabetes mellitus (human, cat, raccoon), but do not cross-react with IAPP from other tested species (mouse, rat, guinea pig, dog).« less
  • A{beta}(1-40) is one of the main components of the fibrils found in amyloid plaques, a hallmark of brains affected by Alzheimer's disease. It is known that prior to the formation of amyloid fibrils in which the peptide adopts a well-ordered intermolecular {beta}-sheet structure, peptide monomers associate forming low and high molecular weight oligomers. These oligomers have been previously described in electron microscopy, AFM, and exclusion chromatography studies. Their specific secondary structures however, have not yet been well established. A major problem when comparing aggregation and secondary structure determinations in concentration-dependent processes such as amyloid aggregation is the different concentration rangemore » required in each type of experiment. In the present study we used the dye Thioflavin T (ThT), Fourier-transform infrared spectroscopy, and electron microscopy in order to structurally characterize the different aggregated species which form during the A{beta}(1-40) fibril formation process. A unique sample containing 90 {mu}M peptide was used. The results show that oligomeric species which form during the lag phase of the aggregation kinetics are a mixture of unordered, helical, and intermolecular non-fibrillar {beta}-structures. The number of oligomers and the amount of non-fibrillar {beta}-structures grows throughout the lag phase and during the elongation phase these non-fibrillar {beta}-structures are transformed into fibrillar (amyloid) {beta}-structures, formed by association of high molecular weight intermediates.« less