Chemistry
The sequence-dependent unfolding pathway plays a critical role in the amyloidogenicity of transthyretin
Document Type
Article
Abstract
Human transthyretin (TTR) is an amyloidogenic protein whose aggregation is associated with several types of amyloid diseases. The following mechanism of TTR amyloid formation has been proposed. TTR tetramer at first dissociates into native monomers, which is the rate-limiting step in fibril formation. The monomeric species then partially unfold to form amyloidogenic intermediates that subsequently undergo a downhill self-assembly process. The amyloid deposit can be facilitated by disease-associated point mutations. However, only subtle structural differences were observed between the crystal structures of the wild type and the disease-associated variants. To investigate how single-point mutations influence the effective energy landscapes of TTR monomers, molecular dynamics (MD) simulations were performed on wild-type TTR and two pathogenic variants. Principal coordinate analysis on MD-generated ensembles has revealed multiple unfolding pathways for each protein. Amyloidogenic intermediates with the dislocated C strand-loop-D strand motif were observed only on the unfolding pathways of V30M and L55P variants and not for wild-type TTR. Our study suggests that the sequence-dependent unfolding pathway plays a crucial role in the amyloidogenicity of TTR. Analyses of side chain concerted motions indicate that pathogenic mutations on "edge strands" disrupt the delicate side chain correlated motions, which in turn may alter the sequence of unfolding events. © 2006 American Chemical Society.
Publication Title
Biochemistry
Publication Date
10-3-2006
Volume
45
Issue
39
First Page
11992
Last Page
12002
ISSN
0006-2960
DOI
10.1021/bi0609927
Keywords
agglomeration, computer simulation, diseases, molecular dynamics, monomers, mutagenesis
Repository Citation
Yang, Mingfeng; Yordanov, Boyan; Levy, Yaakov; Brüschweiler, Rafael; and Huo, Shuanghong, "The sequence-dependent unfolding pathway plays a critical role in the amyloidogenicity of transthyretin" (2006). Chemistry. 105.
https://commons.clarku.edu/chemistry/105
Cross Post Location
Student Publications