Role of the region 23-28 in Abeta fibril formation: insights from simulations of the monomers and dimers of Alzheimer's peptides Abeta40 and Abeta42.
Self-assembly of the 40/42 amino acid Abeta peptide is a key player in Alzheimer's disease. Abeta40 is the most prevalent species, while Abeta42 is the most toxic. It has been suggested that the amino acids 21-30 could nucleate the folding of Abeta monomer and a bent in this region could be the rate-limiting step in Abeta fibril formation. In this study, we review our current understanding of the computer-predicted conformations of amino acids 23-28 in the monomer of Abeta(21-30) and the monomers Abeta40 and Abeta42. On the basis of new simulations on dimers of full-length Abeta, we propose that the rate-limiting step involves the formation of a multimeric beta-sheet spanning the central hydrophobic core (residues 17-21).
Laboratoire de Biochimie Théorique, UPR9080 CNRS, Institut de Biologie Physico-Chimique et Université Paris 7 Denis-Diderot, Paris, France.
Adrien
A
Melquiond
Xiao
X
Dong
Normand
N
Mousseau
Philippe
P
Derreumaux
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D017510:Protein Folding; D017433:Protein Structure, Secondary / Q000502:physiology*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments