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Pathologic polyglutamine aggregation begins with a self-poisoning polymer crystal
A long-standing goal of amyloid research has been to characterize the structural basis of the rate-determining nucleating event. However, the ephemeral nature of nucleation has made this goal unachievable with existing biochemistry, structural biology, and computational approaches. Here, we addresse...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10624427/ https://www.ncbi.nlm.nih.gov/pubmed/37921648 http://dx.doi.org/10.7554/eLife.86939 |
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author | Kandola, Tej Venkatesan, Shriram Zhang, Jiahui Lerbakken, Brooklyn T Von Schulze, Alex Blanck, Jillian F Wu, Jianzheng Unruh, Jay R Berry, Paula Lange, Jeffrey J Box, Andrew C Cook, Malcolm Sagui, Celeste Halfmann, Randal |
author_facet | Kandola, Tej Venkatesan, Shriram Zhang, Jiahui Lerbakken, Brooklyn T Von Schulze, Alex Blanck, Jillian F Wu, Jianzheng Unruh, Jay R Berry, Paula Lange, Jeffrey J Box, Andrew C Cook, Malcolm Sagui, Celeste Halfmann, Randal |
author_sort | Kandola, Tej |
collection | PubMed |
description | A long-standing goal of amyloid research has been to characterize the structural basis of the rate-determining nucleating event. However, the ephemeral nature of nucleation has made this goal unachievable with existing biochemistry, structural biology, and computational approaches. Here, we addressed that limitation for polyglutamine (polyQ), a polypeptide sequence that causes Huntington’s and other amyloid-associated neurodegenerative diseases when its length exceeds a characteristic threshold. To identify essential features of the polyQ amyloid nucleus, we used a direct intracellular reporter of self-association to quantify frequencies of amyloid appearance as a function of concentration, conformational templates, and rational polyQ sequence permutations. We found that nucleation of pathologically expanded polyQ involves segments of three glutamine (Q) residues at every other position. We demonstrate using molecular simulations that this pattern encodes a four-stranded steric zipper with interdigitated Q side chains. Once formed, the zipper poisoned its own growth by engaging naive polypeptides on orthogonal faces, in a fashion characteristic of polymer crystals with intramolecular nuclei. We further show that self-poisoning can be exploited to block amyloid formation, by genetically oligomerizing polyQ prior to nucleation. By uncovering the physical nature of the rate-limiting event for polyQ aggregation in cells, our findings elucidate the molecular etiology of polyQ diseases. |
format | Online Article Text |
id | pubmed-10624427 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-106244272023-11-04 Pathologic polyglutamine aggregation begins with a self-poisoning polymer crystal Kandola, Tej Venkatesan, Shriram Zhang, Jiahui Lerbakken, Brooklyn T Von Schulze, Alex Blanck, Jillian F Wu, Jianzheng Unruh, Jay R Berry, Paula Lange, Jeffrey J Box, Andrew C Cook, Malcolm Sagui, Celeste Halfmann, Randal eLife Structural Biology and Molecular Biophysics A long-standing goal of amyloid research has been to characterize the structural basis of the rate-determining nucleating event. However, the ephemeral nature of nucleation has made this goal unachievable with existing biochemistry, structural biology, and computational approaches. Here, we addressed that limitation for polyglutamine (polyQ), a polypeptide sequence that causes Huntington’s and other amyloid-associated neurodegenerative diseases when its length exceeds a characteristic threshold. To identify essential features of the polyQ amyloid nucleus, we used a direct intracellular reporter of self-association to quantify frequencies of amyloid appearance as a function of concentration, conformational templates, and rational polyQ sequence permutations. We found that nucleation of pathologically expanded polyQ involves segments of three glutamine (Q) residues at every other position. We demonstrate using molecular simulations that this pattern encodes a four-stranded steric zipper with interdigitated Q side chains. Once formed, the zipper poisoned its own growth by engaging naive polypeptides on orthogonal faces, in a fashion characteristic of polymer crystals with intramolecular nuclei. We further show that self-poisoning can be exploited to block amyloid formation, by genetically oligomerizing polyQ prior to nucleation. By uncovering the physical nature of the rate-limiting event for polyQ aggregation in cells, our findings elucidate the molecular etiology of polyQ diseases. eLife Sciences Publications, Ltd 2023-11-03 /pmc/articles/PMC10624427/ /pubmed/37921648 http://dx.doi.org/10.7554/eLife.86939 Text en © 2023, Kandola, Venkatesan et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Structural Biology and Molecular Biophysics Kandola, Tej Venkatesan, Shriram Zhang, Jiahui Lerbakken, Brooklyn T Von Schulze, Alex Blanck, Jillian F Wu, Jianzheng Unruh, Jay R Berry, Paula Lange, Jeffrey J Box, Andrew C Cook, Malcolm Sagui, Celeste Halfmann, Randal Pathologic polyglutamine aggregation begins with a self-poisoning polymer crystal |
title | Pathologic polyglutamine aggregation begins with a self-poisoning polymer crystal |
title_full | Pathologic polyglutamine aggregation begins with a self-poisoning polymer crystal |
title_fullStr | Pathologic polyglutamine aggregation begins with a self-poisoning polymer crystal |
title_full_unstemmed | Pathologic polyglutamine aggregation begins with a self-poisoning polymer crystal |
title_short | Pathologic polyglutamine aggregation begins with a self-poisoning polymer crystal |
title_sort | pathologic polyglutamine aggregation begins with a self-poisoning polymer crystal |
topic | Structural Biology and Molecular Biophysics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10624427/ https://www.ncbi.nlm.nih.gov/pubmed/37921648 http://dx.doi.org/10.7554/eLife.86939 |
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