Sequence-based modeling of Abeta42 soluble oligomers.
Abeta fibrils, which are central to the pathology of Alzheimer's disease, form a cross-beta-structure that contains likely parallel beta-sheets with a salt bridge between residues Asp23 and Lys28. Recent studies suggest that soluble oligomers of amyloid peptides have neurotoxic effects in cell cultures, raising the interest in studying the structures of these intermediate forms. Here, we present three models of possible soluble Abeta forms based on the sequences similarities, assumed to support local structural similarities, of the Abeta peptide with fragments of three proteins (adhesin, Semliki Forest virus capsid protein, and transthyretin). These three models share a similar structure in the C-terminal region composed of two beta-strands connected by a loop, which contain the Asp23-Lys28 salt bridge. This segment is also structurally well conserved in Abeta fibril forms. Differences between the three monomeric models occur in the N-terminal region and in the C-terminal tail. These three models might sample some of the most stable conformers of the soluble Abeta peptide within oligomeric assemblies, which were modeled here in the form of dimers, trimers, tetramers, and hexamers. The consistency of these models is discussed with respect to available experimental and theoretical data.
Dulin
Fabienne
F
Département de Biologie Structurale, IMPMC, CNRS UMR7590, Universités Pierre et Marie Curie-Paris 6 et Denis Diderot-Paris 7, F-75005 France.
Callebaut
Isabelle
I
Colloc'h
Nathalie
N
Mornon
Jean-Paul
JP
D018830:Adhesins, Escherichia coli / Q000737:chemistry; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D036022:Capsid Proteins / Q000737:chemistry; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry*; D011228:Prealbumin / Q000737:chemistry; D011487:Protein Conformation; D017510:Protein Folding; D012672:Semliki forest virus / Q000737:chemistry / Q000201:enzymology; D016415:Sequence Alignment
D018830:Adhesins, Escherichia coli; D016229:Amyloid beta-Peptides; D036022:Capsid Proteins; D010446:Peptide Fragments; D011228:Prealbumin; C075222:amyloid beta-protein (1-42)