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A generic approach to decipher the mechanistic pathway of heterogeneous protein aggregation kinetics

Amyloid formation is a generic property of many protein/polypeptide chains. A broad spectrum of proteins, despite having diversity in the inherent precursor sequence and heterogeneity present in the mechanism of aggregation produces a common cross β-spine structure that is often associated with seve...

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Detalles Bibliográficos
Autores principales: Tikader, Baishakhi, Maji, Samir K., Kar, Sandip
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528017/
https://www.ncbi.nlm.nih.gov/pubmed/34777773
http://dx.doi.org/10.1039/d1sc03190b
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author Tikader, Baishakhi
Maji, Samir K.
Kar, Sandip
author_facet Tikader, Baishakhi
Maji, Samir K.
Kar, Sandip
author_sort Tikader, Baishakhi
collection PubMed
description Amyloid formation is a generic property of many protein/polypeptide chains. A broad spectrum of proteins, despite having diversity in the inherent precursor sequence and heterogeneity present in the mechanism of aggregation produces a common cross β-spine structure that is often associated with several human diseases. However, a general modeling framework to interpret amyloid formation remains elusive. Herein, we propose a data-driven mathematical modeling approach that elucidates the most probable interaction network for the aggregation of a group of proteins (α-synuclein, Aβ42, Myb, and TTR proteins) by considering an ensemble set of network models, which include most of the mechanistic complexities and heterogeneities related to amyloidogenesis. The best-fitting model efficiently quantifies various timescales involved in the process of amyloidogenesis and explains the mechanistic basis of the monomer concentration dependency of amyloid-forming kinetics. Moreover, the present model reconciles several mutant studies and inhibitor experiments for the respective proteins, making experimentally feasible non-intuitive predictions, and provides further insights about how to fine-tune the various microscopic events related to amyloid formation kinetics. This might have an application to formulate better therapeutic measures in the future to counter unwanted amyloidogenesis. Importantly, the theoretical method used here is quite general and can be extended for any amyloid-forming protein.
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spelling pubmed-85280172021-11-12 A generic approach to decipher the mechanistic pathway of heterogeneous protein aggregation kinetics Tikader, Baishakhi Maji, Samir K. Kar, Sandip Chem Sci Chemistry Amyloid formation is a generic property of many protein/polypeptide chains. A broad spectrum of proteins, despite having diversity in the inherent precursor sequence and heterogeneity present in the mechanism of aggregation produces a common cross β-spine structure that is often associated with several human diseases. However, a general modeling framework to interpret amyloid formation remains elusive. Herein, we propose a data-driven mathematical modeling approach that elucidates the most probable interaction network for the aggregation of a group of proteins (α-synuclein, Aβ42, Myb, and TTR proteins) by considering an ensemble set of network models, which include most of the mechanistic complexities and heterogeneities related to amyloidogenesis. The best-fitting model efficiently quantifies various timescales involved in the process of amyloidogenesis and explains the mechanistic basis of the monomer concentration dependency of amyloid-forming kinetics. Moreover, the present model reconciles several mutant studies and inhibitor experiments for the respective proteins, making experimentally feasible non-intuitive predictions, and provides further insights about how to fine-tune the various microscopic events related to amyloid formation kinetics. This might have an application to formulate better therapeutic measures in the future to counter unwanted amyloidogenesis. Importantly, the theoretical method used here is quite general and can be extended for any amyloid-forming protein. The Royal Society of Chemistry 2021-09-03 /pmc/articles/PMC8528017/ /pubmed/34777773 http://dx.doi.org/10.1039/d1sc03190b Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Chemistry
Tikader, Baishakhi
Maji, Samir K.
Kar, Sandip
A generic approach to decipher the mechanistic pathway of heterogeneous protein aggregation kinetics
title A generic approach to decipher the mechanistic pathway of heterogeneous protein aggregation kinetics
title_full A generic approach to decipher the mechanistic pathway of heterogeneous protein aggregation kinetics
title_fullStr A generic approach to decipher the mechanistic pathway of heterogeneous protein aggregation kinetics
title_full_unstemmed A generic approach to decipher the mechanistic pathway of heterogeneous protein aggregation kinetics
title_short A generic approach to decipher the mechanistic pathway of heterogeneous protein aggregation kinetics
title_sort generic approach to decipher the mechanistic pathway of heterogeneous protein aggregation kinetics
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528017/
https://www.ncbi.nlm.nih.gov/pubmed/34777773
http://dx.doi.org/10.1039/d1sc03190b
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