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Network of hotspot interactions cluster tau amyloid folds

Cryogenic electron microscopy has revealed unprecedented molecular insight into the conformations of β-sheet-rich protein amyloids linked to neurodegenerative diseases. It remains unknown how a protein can adopt a diversity of folds and form multiple distinct fibrillar structures. Here we develop an...

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Autores principales: Mullapudi, Vishruth, Vaquer-Alicea, Jaime, Bommareddy, Vaibhav, Vega, Anthony R., Ryder, Bryan D., White, Charles L., Diamond, Marc. I., Joachimiak, Lukasz A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9935906/
https://www.ncbi.nlm.nih.gov/pubmed/36797278
http://dx.doi.org/10.1038/s41467-023-36572-3
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author Mullapudi, Vishruth
Vaquer-Alicea, Jaime
Bommareddy, Vaibhav
Vega, Anthony R.
Ryder, Bryan D.
White, Charles L.
Diamond, Marc. I.
Joachimiak, Lukasz A.
author_facet Mullapudi, Vishruth
Vaquer-Alicea, Jaime
Bommareddy, Vaibhav
Vega, Anthony R.
Ryder, Bryan D.
White, Charles L.
Diamond, Marc. I.
Joachimiak, Lukasz A.
author_sort Mullapudi, Vishruth
collection PubMed
description Cryogenic electron microscopy has revealed unprecedented molecular insight into the conformations of β-sheet-rich protein amyloids linked to neurodegenerative diseases. It remains unknown how a protein can adopt a diversity of folds and form multiple distinct fibrillar structures. Here we develop an in silico alanine scan method to estimate the relative energetic contribution of each amino acid in an amyloid assembly. We apply our method to twenty-seven ex vivo and in vitro fibril structural polymorphs of the microtubule-associated protein tau. We uncover networks of energetically important interactions involving amyloid-forming motifs that stabilize the different fibril folds. We evaluate our predictions in cellular and in vitro aggregation assays. Using a machine learning approach, we classify the structures based on residue energetics to identify distinguishing and unifying features. Our energetic profiling suggests that minimal sequence elements control the stability of tau fibrils, allowing future design of protein sequences that fold into unique structures.
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spelling pubmed-99359062023-02-18 Network of hotspot interactions cluster tau amyloid folds Mullapudi, Vishruth Vaquer-Alicea, Jaime Bommareddy, Vaibhav Vega, Anthony R. Ryder, Bryan D. White, Charles L. Diamond, Marc. I. Joachimiak, Lukasz A. Nat Commun Article Cryogenic electron microscopy has revealed unprecedented molecular insight into the conformations of β-sheet-rich protein amyloids linked to neurodegenerative diseases. It remains unknown how a protein can adopt a diversity of folds and form multiple distinct fibrillar structures. Here we develop an in silico alanine scan method to estimate the relative energetic contribution of each amino acid in an amyloid assembly. We apply our method to twenty-seven ex vivo and in vitro fibril structural polymorphs of the microtubule-associated protein tau. We uncover networks of energetically important interactions involving amyloid-forming motifs that stabilize the different fibril folds. We evaluate our predictions in cellular and in vitro aggregation assays. Using a machine learning approach, we classify the structures based on residue energetics to identify distinguishing and unifying features. Our energetic profiling suggests that minimal sequence elements control the stability of tau fibrils, allowing future design of protein sequences that fold into unique structures. Nature Publishing Group UK 2023-02-16 /pmc/articles/PMC9935906/ /pubmed/36797278 http://dx.doi.org/10.1038/s41467-023-36572-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Mullapudi, Vishruth
Vaquer-Alicea, Jaime
Bommareddy, Vaibhav
Vega, Anthony R.
Ryder, Bryan D.
White, Charles L.
Diamond, Marc. I.
Joachimiak, Lukasz A.
Network of hotspot interactions cluster tau amyloid folds
title Network of hotspot interactions cluster tau amyloid folds
title_full Network of hotspot interactions cluster tau amyloid folds
title_fullStr Network of hotspot interactions cluster tau amyloid folds
title_full_unstemmed Network of hotspot interactions cluster tau amyloid folds
title_short Network of hotspot interactions cluster tau amyloid folds
title_sort network of hotspot interactions cluster tau amyloid folds
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9935906/
https://www.ncbi.nlm.nih.gov/pubmed/36797278
http://dx.doi.org/10.1038/s41467-023-36572-3
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