Chemistry

Intrinsic versus mutation dependent instability/flexibility: A comparative analysis of the structure and dynamics of wild-type transthyretin and its pathogenic variants

Document Type

Article

Abstract

Transthyretin (TTR) is one of the about 20 known human proteins associated with amyloidosis which is characterized by the accumulation of amyloid fibrils in tissues or extracellular matrix surrounding vital organs. Unlike Alzheimer's fibrils that comprise a fragment of a large precursor protein, TTR amyloid fibrils are composed of both full-length protein and fragments of the molecule. The native state of TTR is a homotetramer with eight β-strands organized into a β-sandwich in each monomer. To elucidate the structural reorganization mechanisms preceding amyloid formation, it is important to characterize the dynamic features of the wild-type native state as well as to reveal the influence of disease-associated mutations on the structure and dynamics. Molecular dynamics (MD) simulations complement X-ray crystallography and D-H exchange to capture the intrinsically unstable/flexible sites of the wild-type as well as the mutation dependent unstable sites of the pathogenic variants. Our results of MD simulations have shown that the Leu55 → Pro (L55P) mutation occurs in an intrinsically unstable site, leading to substantial local and global structural changes. This observation supports the early speculation that the C-strand-loop-D-strand rearrangement leads to the formation of amyloidogenic intermediates. In addition to the D strand, the α-helical region and the strands at the monomer-monomer interface are also intrinsically unstable. The central channel of L55P-TTR undergoes opening and closing fluctuations, which may provide an explanation for the fact that while the mutation is far from the channel, the mutant shows a substantial low binding affinity of thyroxine. © 2004 Elsevier Inc. All rights reserved.

Publication Title

Journal of Structural Biology

Publication Date

11-2004

Volume

148

Issue

2

First Page

153

Last Page

168

ISSN

1047-8477

DOI

10.1016/j.jsb.2004.06.007

Keywords

amyloid deposit, conformational change, human transthyretin, molecular dynamics simulation, single-point mutation

Cross Post Location

Student Publications

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