Amyloidogenicity at a Distance: How Distal Protein Regions Modulate Aggregation in Disease

Research output: Contribution to journalReview ArticleResearchpeer-review

Abstract

The misfolding of proteins to form amyloid is a key pathological feature of several progressive, and currently incurable, diseases. A mechanistic understanding of the pathway from soluble, native protein to insoluble amyloid is crucial for therapeutic design, and recent efforts have helped to elucidate the key molecular events that trigger protein misfolding. Generally, either global or local structural perturbations occur early in amyloidogenesis to expose aggregation-prone regions of the protein that can then self-associate to form toxic oligomers. Surprisingly, these initiating structural changes are often caused or influenced by protein regions distal to the classically amyloidogenic sequences. Understanding the importance of these distal regions in the pathogenic process has highlighted many remaining knowledge gaps regarding the precise molecular events that occur in classic aggregation pathways. In this review, we discuss how these distal regions can influence aggregation in disease and the recent technical and conceptual advances that have allowed this insight.

Original languageEnglish
Pages (from-to)1289-1304
Number of pages16
JournalJournal of Molecular Biology
Volume429
Issue number9
DOIs
Publication statusPublished - 5 May 2017

Keywords

  • amyloid
  • misfolding
  • polyglutamine
  • α-synuclein
  • β2-microglobulin

Cite this

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title = "Amyloidogenicity at a Distance: How Distal Protein Regions Modulate Aggregation in Disease",
abstract = "The misfolding of proteins to form amyloid is a key pathological feature of several progressive, and currently incurable, diseases. A mechanistic understanding of the pathway from soluble, native protein to insoluble amyloid is crucial for therapeutic design, and recent efforts have helped to elucidate the key molecular events that trigger protein misfolding. Generally, either global or local structural perturbations occur early in amyloidogenesis to expose aggregation-prone regions of the protein that can then self-associate to form toxic oligomers. Surprisingly, these initiating structural changes are often caused or influenced by protein regions distal to the classically amyloidogenic sequences. Understanding the importance of these distal regions in the pathogenic process has highlighted many remaining knowledge gaps regarding the precise molecular events that occur in classic aggregation pathways. In this review, we discuss how these distal regions can influence aggregation in disease and the recent technical and conceptual advances that have allowed this insight.",
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Amyloidogenicity at a Distance : How Distal Protein Regions Modulate Aggregation in Disease. / Lucato, Christina M.; Lupton, Christopher J.; Halls, Michelle L.; Ellisdon, Andrew M.

In: Journal of Molecular Biology, Vol. 429, No. 9, 05.05.2017, p. 1289-1304.

Research output: Contribution to journalReview ArticleResearchpeer-review

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T1 - Amyloidogenicity at a Distance

T2 - How Distal Protein Regions Modulate Aggregation in Disease

AU - Lucato, Christina M.

AU - Lupton, Christopher J.

AU - Halls, Michelle L.

AU - Ellisdon, Andrew M.

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AB - The misfolding of proteins to form amyloid is a key pathological feature of several progressive, and currently incurable, diseases. A mechanistic understanding of the pathway from soluble, native protein to insoluble amyloid is crucial for therapeutic design, and recent efforts have helped to elucidate the key molecular events that trigger protein misfolding. Generally, either global or local structural perturbations occur early in amyloidogenesis to expose aggregation-prone regions of the protein that can then self-associate to form toxic oligomers. Surprisingly, these initiating structural changes are often caused or influenced by protein regions distal to the classically amyloidogenic sequences. Understanding the importance of these distal regions in the pathogenic process has highlighted many remaining knowledge gaps regarding the precise molecular events that occur in classic aggregation pathways. In this review, we discuss how these distal regions can influence aggregation in disease and the recent technical and conceptual advances that have allowed this insight.

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