The sequence-dependent unfolding pathway plays a critical role in the amyloidogenicity of transthyretin.
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.
Yang
Mingfeng
M
Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, Worcester, Massachusetts 01610, USA.
Yordanov
Boyan
B
Levy
Yaakov
Y
Brüschweiler
Rafael
R
Huo
Shuanghong
S
D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D000686:Amyloidosis / Q000378:metabolism; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D011228:Prealbumin / Q000737:chemistry* / Q000378:metabolism; D017510:Protein Folding
D000682:Amyloid; D011228:Prealbumin