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

Different disease-causing mutations in transthyretin trigger the same conformational conversion. Research Abstract Details 

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Different disease-causing mutations in transthyretin trigger the same conformational conversion. Abstract Text:

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 beta-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 beta-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.

Different disease-causing mutations in transthyretin trigger the same conformational conversion. Publishing Authors By Initials

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Different disease-causing mutations in transthyretin trigger the same conformational conversion. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Protein engineering, design & selection : PEDS

VOLUME: 21

Page Numbers: 187-95

Journal Abbreviation: Protein Eng. Des. Sel.

ISSN: 1741-0126

DAY: 13

MONTH: 02

YEAR: 2008

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

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LANGUAGE: eng

NlmUniqueID: 101186484

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Grant and Affiliation Information for Different disease-causing mutations in transthyretin trigger the same conformational conversion.

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

Country: England

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MEDLINETA: Protein Eng Des Sel

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