Anatomy of an amyloidogenic intermediate: conversion of beta-sheet to alpha-sheet structure in transthyretin at acidic pH.
The homotetramer of transthyretin (TTR) dissociates into a monomeric amyloidogenic intermediate that self-assembles into amyloid fibrils at low pH. We have performed molecular dynamics simulations of monomeric TTR at neutral and low pH at physiological (310 K) and very elevated temperature (498 K). In the low-pH simulations at both temperatures, one of the two beta-sheets (strands CBEF) becomes disrupted, and alpha-sheet structure forms in the other sheet (strands DAGH). alpha-sheet is formed by alternating alphaL and alphaR residues, and it was first proposed by Pauling and Corey. Overall, the simulations are in agreement with the available experimental observations, including solid-state NMR results for a TTR-peptide amyloid. In addition, they provide a unique explanation for the results of hydrogen exchange experiments of the amyloidogenic intermediate-results that are difficult to explain with beta-structure. We propose that alpha-sheet may represent a key pathological conformation during amyloidogenesis.
Department of Medicinal Chemistry, Box 357610, University of Washington, Seattle, WA 98195, USA.
Roger S
RS
Armen
Darwin O V
DO
Alonso
Valerie
V
Daggett
D000682:Amyloid / Q000737:chemistry*; D000686:Amyloidosis / Q000473:pathology; D003461:Crystallography; D006801:Humans; D006863:Hydrogen-Ion Concentration; D011228:Prealbumin / Q000737:chemistry*; D017433:Protein Structure, Secondary; D013696:Temperature
D000682:Amyloid; D011228:Prealbumin