Molecular insights into the surface-catalyzed secondary nucleation of amyloid-40 (A40) by the peptide fragment A16–22

Samuel J. Bunce; Yiming Wang; Katie L. Stewart; Alison E. Ashcroft; Sheena E. Radford; Carol K. Hall; Andrew J. Wilson

doi:10.1126/sciadv.aav8216

Molecular insights into the surface-catalyzed secondary nucleation of amyloid-₄₀ (A₄₀) by the peptide fragment A_16–22

Samuel J. Bunce, Yiming Wang, Katie L. Stewart, Alison E. Ashcroft, Sheena E. Radford^*, Carol K. Hall, Andrew J. Wilson

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

43 Citations (Scopus)

Abstract

Understanding the structural mechanism by which proteins and peptides aggregate is crucial, given the role of fibrillar aggregates in debilitating amyloid diseases and bioinspired materials. Yet, this is a major challenge as the assembly involves multiple heterogeneous and transient intermediates. Here, we analyze the co-aggregation of A₄₀ and A_16–22, two widely studied peptide fragments of A₄₂ implicated in Alzheimer’s disease. We demonstrate that A_16–22 increases the aggregation rate of A₄₀ through a surface-catalyzed secondary nucleation mechanism. Discontinuous molecular dynamics simulations allowed aggregation to be tracked from the initial random coil monomer to the catalysis of nucleation on the fibril surface. Together, the results provide insight into how dynamic interactions between A₄₀ monomers/oligomers on the surface of preformed A_16–22 fibrils nucleate A₄₀ amyloid assembly. This new understanding may facilitate development of surfaces designed to enhance or suppress secondary nucleation and hence to control the rates and products of fibril assembly.

Original language	English
Article number	eaav8216
Journal	Science Advances
Volume	5
Issue number	6
DOIs	https://doi.org/10.1126/sciadv.aav8216
Publication status	Published - 2019

Bibliographical note

Funding Information:
We thank M. Iadanza for help with taking and processing the EM images. We also thank N. Khan for excellent technical support and members of our laboratories for excellent discussions during the course of the work. This work was supported by NIH grant R01 EB006006 and, in part, by National Science Foundation (NSF) Research Triangle Materials Research Science and Engineering Centers (MRSEC) grant DMR-1121107, NSF grant CBET 581606, and EPSRC grants EP/N035267/1, EP/N013573/1, and EP/KO39292/1. S.E.R. acknowledges funding from the ERC (grant agreement number 322408) and the Wellcome Trust (204963). S.J.B. gratefully acknowledges BBSRC for PhD studentship grant BB/J014443/1. The EM was purchased with funding from the Wellcome Trust (108466/Z/15/Z and 094232/Z/10/Z). Y.W. and C.K.H. gratefully acknowledge the support of a Cheney Visiting Scholar Fellowship from University of Leeds.

Publisher Copyright:
Copyright © 2019 The Authors,

ASJC Scopus subject areas

General

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10.1126/sciadv.aav8216

Cite this

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title = "Molecular insights into the surface-catalyzed secondary nucleation of amyloid-40 (A40) by the peptide fragment A16–22",

abstract = "Understanding the structural mechanism by which proteins and peptides aggregate is crucial, given the role of fibrillar aggregates in debilitating amyloid diseases and bioinspired materials. Yet, this is a major challenge as the assembly involves multiple heterogeneous and transient intermediates. Here, we analyze the co-aggregation of A40 and A16–22, two widely studied peptide fragments of A42 implicated in Alzheimer{\textquoteright}s disease. We demonstrate that A16–22 increases the aggregation rate of A40 through a surface-catalyzed secondary nucleation mechanism. Discontinuous molecular dynamics simulations allowed aggregation to be tracked from the initial random coil monomer to the catalysis of nucleation on the fibril surface. Together, the results provide insight into how dynamic interactions between A40 monomers/oligomers on the surface of preformed A16–22 fibrils nucleate A40 amyloid assembly. This new understanding may facilitate development of surfaces designed to enhance or suppress secondary nucleation and hence to control the rates and products of fibril assembly.",

author = "Bunce, {Samuel J.} and Yiming Wang and Stewart, {Katie L.} and Ashcroft, {Alison E.} and Radford, {Sheena E.} and Hall, {Carol K.} and Wilson, {Andrew J.}",

note = "Funding Information: We thank M. Iadanza for help with taking and processing the EM images. We also thank N. Khan for excellent technical support and members of our laboratories for excellent discussions during the course of the work. This work was supported by NIH grant R01 EB006006 and, in part, by National Science Foundation (NSF) Research Triangle Materials Research Science and Engineering Centers (MRSEC) grant DMR-1121107, NSF grant CBET 581606, and EPSRC grants EP/N035267/1, EP/N013573/1, and EP/KO39292/1. S.E.R. acknowledges funding from the ERC (grant agreement number 322408) and the Wellcome Trust (204963). S.J.B. gratefully acknowledges BBSRC for PhD studentship grant BB/J014443/1. The EM was purchased with funding from the Wellcome Trust (108466/Z/15/Z and 094232/Z/10/Z). Y.W. and C.K.H. gratefully acknowledge the support of a Cheney Visiting Scholar Fellowship from University of Leeds. Publisher Copyright: Copyright {\textcopyright} 2019 The Authors,",

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AU - Radford, Sheena E.

AU - Hall, Carol K.

AU - Wilson, Andrew J.

N1 - Funding Information: We thank M. Iadanza for help with taking and processing the EM images. We also thank N. Khan for excellent technical support and members of our laboratories for excellent discussions during the course of the work. This work was supported by NIH grant R01 EB006006 and, in part, by National Science Foundation (NSF) Research Triangle Materials Research Science and Engineering Centers (MRSEC) grant DMR-1121107, NSF grant CBET 581606, and EPSRC grants EP/N035267/1, EP/N013573/1, and EP/KO39292/1. S.E.R. acknowledges funding from the ERC (grant agreement number 322408) and the Wellcome Trust (204963). S.J.B. gratefully acknowledges BBSRC for PhD studentship grant BB/J014443/1. The EM was purchased with funding from the Wellcome Trust (108466/Z/15/Z and 094232/Z/10/Z). Y.W. and C.K.H. gratefully acknowledge the support of a Cheney Visiting Scholar Fellowship from University of Leeds. Publisher Copyright: Copyright © 2019 The Authors,

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N2 - Understanding the structural mechanism by which proteins and peptides aggregate is crucial, given the role of fibrillar aggregates in debilitating amyloid diseases and bioinspired materials. Yet, this is a major challenge as the assembly involves multiple heterogeneous and transient intermediates. Here, we analyze the co-aggregation of A40 and A16–22, two widely studied peptide fragments of A42 implicated in Alzheimer’s disease. We demonstrate that A16–22 increases the aggregation rate of A40 through a surface-catalyzed secondary nucleation mechanism. Discontinuous molecular dynamics simulations allowed aggregation to be tracked from the initial random coil monomer to the catalysis of nucleation on the fibril surface. Together, the results provide insight into how dynamic interactions between A40 monomers/oligomers on the surface of preformed A16–22 fibrils nucleate A40 amyloid assembly. This new understanding may facilitate development of surfaces designed to enhance or suppress secondary nucleation and hence to control the rates and products of fibril assembly.

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