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 »
- Authors:
-
- Imperial College, London (United Kingdom). Inst. of Biomedical Engineering, Dept. of Materials and Dept. of Bioengineering
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Foundry
- 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); 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. https://doi.org/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. https://doi.org/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},
url = {https://www.osti.gov/biblio/1416928},
journal = {ACS Nano},
issn = {1936-0851},
number = 9,
volume = 11,
place = {United States},
year = {Thu Aug 03 00:00:00 EDT 2017},
month = {Thu Aug 03 00:00:00 EDT 2017}
}
Web of Science
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