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The polyglutamine amyloid nucleus in living cells is a monomer with competing dimensions of order

Tej Kandola, Shriram Venkatesan, Jiahui Zhang, Brooklyn Lerbakken, Jillian F Blanck, Jianzheng Wu, Jay Unruh, Paula Berry, Jeffrey J. Lange, Alex Von Schulze, Andrew Box, Malcolm Cook, Celeste Sagui, View ORCID ProfileRandal Halfmann
doi: https://doi.org/10.1101/2021.08.29.458132
Tej Kandola
1Stowers Institute for Medical Research, Kansas City, MO 64110, USA
2The Open University, Milton Keyes, MK7 6AA, UK
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Shriram Venkatesan
1Stowers Institute for Medical Research, Kansas City, MO 64110, USA
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Jiahui Zhang
3Department of Physics, North Carolina State University, Raleigh, NC 27695, USA
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Brooklyn Lerbakken
1Stowers Institute for Medical Research, Kansas City, MO 64110, USA
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Jillian F Blanck
1Stowers Institute for Medical Research, Kansas City, MO 64110, USA
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Jianzheng Wu
1Stowers Institute for Medical Research, Kansas City, MO 64110, USA
4Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA
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Jay Unruh
1Stowers Institute for Medical Research, Kansas City, MO 64110, USA
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Paula Berry
1Stowers Institute for Medical Research, Kansas City, MO 64110, USA
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Jeffrey J. Lange
1Stowers Institute for Medical Research, Kansas City, MO 64110, USA
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Alex Von Schulze
1Stowers Institute for Medical Research, Kansas City, MO 64110, USA
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Andrew Box
1Stowers Institute for Medical Research, Kansas City, MO 64110, USA
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Malcolm Cook
1Stowers Institute for Medical Research, Kansas City, MO 64110, USA
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Celeste Sagui
3Department of Physics, North Carolina State University, Raleigh, NC 27695, USA
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Randal Halfmann
1Stowers Institute for Medical Research, Kansas City, MO 64110, USA
4Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA
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  • ORCID record for Randal Halfmann
  • For correspondence: rhn@stowers.org
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Abstract

A long-standing goal of the study of amyloids has been to characterize the structural basis of the rate-determining nucleating event. However, the ephemeral nature of that event has made it inaccessible to classical biochemistry, structural biology, and computational approaches. Here, we addressed that limitation by measuring the dependence of amyloid formation on concentration and conformational templates in living cells, whose volumes are sufficiently small to resolve the outcomes of independent nucleation events. We characterized numerous rationally designed sequence variants of polyglutamine (polyQ), a polypeptide that precipitates Huntington’s and other amyloid-associated neurodegenerative diseases when its length exceeds a characteristic threshold. This effort uncovered a pattern of approximately twelve Qs, only for polypeptides exceeding the clinical length threshold, that allow for amyloid nucleation to occur spontaneously within single polypeptides. Nucleation was inhibited by intermolecular phase separation. Using atomistic molecular dynamics simulations, we found that the pattern encodes a minimal steric zipper of interdigitated side chains. Lateral growth of the steric zipper competed with axial growth to produce “pre-amyloid” oligomers. By illuminating the structural mechanism of polyQ amyloid formation in cells, our findings reveal a potential molecular etiology for polyQ diseases, and may provide a roadmap for the design of new therapies.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • This version of the manuscript has been revised to include additional citations and improve readability.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted September 12, 2021.
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The polyglutamine amyloid nucleus in living cells is a monomer with competing dimensions of order
Tej Kandola, Shriram Venkatesan, Jiahui Zhang, Brooklyn Lerbakken, Jillian F Blanck, Jianzheng Wu, Jay Unruh, Paula Berry, Jeffrey J. Lange, Alex Von Schulze, Andrew Box, Malcolm Cook, Celeste Sagui, Randal Halfmann
bioRxiv 2021.08.29.458132; doi: https://doi.org/10.1101/2021.08.29.458132
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The polyglutamine amyloid nucleus in living cells is a monomer with competing dimensions of order
Tej Kandola, Shriram Venkatesan, Jiahui Zhang, Brooklyn Lerbakken, Jillian F Blanck, Jianzheng Wu, Jay Unruh, Paula Berry, Jeffrey J. Lange, Alex Von Schulze, Andrew Box, Malcolm Cook, Celeste Sagui, Randal Halfmann
bioRxiv 2021.08.29.458132; doi: https://doi.org/10.1101/2021.08.29.458132

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