Issue 40, 2021

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

Abstract

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.

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

Supplementary files

Article information

Article type
Edge Article
Submitted
11 Jun 2021
Accepted
01 Sep 2021
First published
03 Sep 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2021,12, 13530-13545

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

B. Tikader, S. K. Maji and S. Kar, Chem. Sci., 2021, 12, 13530 DOI: 10.1039/D1SC03190B

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