NR AHZL
AU Massi,F.; Straub,J.E.
TI Energy landscape theory for Alzheimer's amyloid beta-peptide fibril elongation
QU Proteins 2001 Feb 1; 42(2): 217-29
PT journal article
AB Recent experiments on the kinetics of deposition and fibril elongation of the Alzheimer's beta-amyloid peptide on preexisting fibrils are analyzed. A mechanism is developed based on the dock-and-lock scheme recently proposed by Maggio and coworkers to organize their experimental observations of the kinetics of deposition of beta-peptide on preexisting amyloid fibrils and deposits. Our mechanism includes channels for (1) a one-step prion-like direct deposition on fibrils of activated monomeric peptide in solution, and (2) a two-step deposition of unactivated peptide on fibrils and subsequent reorganization of the peptide-fibril complex. In this way, the mechanism and implied "energy landscape" unify a number of schemes proposed to describe the process of fibril elongation. This beta-amyloid landscape mechanism (beta ALM) is found to be in good agreement with existing experimental data. A number of experimental tests of the mechanism are proposed. The mechanism leads to a clear definition of overall equilibrium or rate constants in terms of the energetics of the elementary underlying processes. Analysis of existing experimental data suggests that fibril elongation occurs through a two-step mechanism of nonspecific peptide absorption and reorganization. The mechanism predicts a turnover in the rate of fibril elongation as a function of temperature and denaturant concentration. Proteins 2001;42:217-229.
MH Alzheimer Disease/*metabolism; Amyloid beta-Protein/*chemistry/genetics; Comparative Study; Cross-Linking Reagents/chemistry; Diffusion; Human; Kinetics; Models, Chemical; Molecular Conformation; Mutation; Peptides/chemistry; Peptides, Cyclic/chemistry; Protein Denaturation; Protein Folding; Solvents/chemistry; Support, Non-U.S. Gov't; Support, U.S. Gov't, Non-P.H.S.; Temperature; Thermodynamics; Viscosity
AD Department of Chemistry, Boston University, Boston, Massachusetts 02115, USA
SP englisch
PO USA