Open AccessPauling and Corey's α-pleated sheet structure may define the prefibrillar amyloidogenic intermediate in amyloid disease
Author(s) -
Roger S. Armen,
Mari L. DeMarco,
Darwin O. V. Alonso,
Valerie Daggett
Publication year - 2004
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0401781101
Subject(s) - chemistry , beta sheet , transthyretin , lysozyme , fibril , amyloid disease , protein secondary structure , amyloid (mycology) , protein structure , denaturation (fissile materials) , biophysics , conformational change , amyloidosis , crystallography , hydrogen bond , amyloid fibril , stereochemistry , biochemistry , amyloid β , molecule , biology , medicine , inorganic chemistry , disease , pathology , nuclear chemistry , endocrinology , organic chemistry
Transthyretin, beta(2)-microglobulin, lysozyme, and the prion protein are four of the best-characterized proteins implicated in amyloid disease. Upon partial acid denaturation, these proteins undergo conformational change into an amyloidogenic intermediate that can self-assemble into amyloid fibrils. Many experiments have shown that pH-mediated changes in structure are required for the formation of the amyloidogeneic intermediate, but it has proved impossible to characterize these conformational changes at high resolution using experimental means. To probe these conformational changes at atomic resolution, we have performed molecular dynamics simulations of these proteins at neutral and low pH. In low-pH simulations of all four proteins, we observe the formation of alpha-pleated sheet secondary structure, which was first proposed by L. Pauling and R. B. Corey [(1951) Proc. Natl. Acad. Sci. USA 37, 251-256]. In all beta-sheet proteins, transthyretin and beta(2)-microglobulin, alpha-pleated sheet structure formed over the strands that are highly protected in hydrogen-exchange experiments probing amyloidogenic conditions. In lysozyme and the prion protein, alpha-sheets formed in the specific regions of the protein implicated in the amyloidogenic conversion. We propose that the formation of alpha-pleated sheet structure may be a common conformational transition in amyloidosis.