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PEDS Advance Access published online on February 13, 2008
Protein Engineering Design and Selection, doi:10.1093/protein/gzm086
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Article

Different disease-causing mutations in transthyretin trigger the same conformational conversion

Robert E. Steward1, Roger S. Armen2 and Valerie Daggett3

Department of Bioengineering, University of Washington, Box 355061, Seattle, WA 98195-5061, USA

3 To whom correspondence should be addressed. E-mail: daggett{at}u.washington.edu

Transthyretin (TTR)-containing amyloid fibrils are deposited in cardiac tissue as a natural consequence of aging. A large number of inherited mutations lead to amyloid diseases by accelerating TTR deposition in other organs. Amyloid formation is preceded by a disruption of the quaternary structure of TTR and conformational changes in the monomer. To study conformational changes preceding the formation of amyloid, we performed molecular dynamics simulations of the wild-type monomer, amyloidogenic variants (V30M, L55P, V122I) and a protective variant (T119M) at neutral and low pH. At low pH, the D strand dissociated from the β-sheet to expose the A strand, consistent with experimental studies. In amyloidogenic variants and in the wild-type at low pH, there was a conformational change in the β-sheets into {alpha}-sheet via peptide bond flips that was not observed at neutral pH in the wild-type monomer. The same residues participated in conversion in each amyloidogenic variant simulation, originating in the G strand between residues 106 and 109, with accelerated conversion at low pH. The T119M protective variant changed the local conformation of the H strand and suppressed the conversion observed in amyloidogenic variants.

Keywords: amyloidogenic intermediate/molecular dynamics/transthyretin

Received December 4, 2007; accepted December 6, 2007.

1 Present address: Tessella Plc, 3 Vineyard Chambers, Abingdon, Oxfordshire OX 14 3PX, UK

2 Present address: Department of Molecular Biology, The Scripps Research Institute, 11550 North Torrey Pines Road, La Jolla, CA 92037, USA


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