2007/10/05 by Menachem J. Gunzburg, Matthew A. Perugini, Geoffrey J. Howlett · 1 citation
Medicine · Biochemistry, Genetics and Molecular Biology · Computer Science · Chemistry · Mathematics · #Alzheimer's disease research and treatments #Protein Structure and Dynamics #Computational Drug Discovery Methods #Amyloid fibril #Basis (linear algebra) #Amyloid (mycology) #Fibril #Chemistry #Apolipoprotein B #Apolipoprotein E #Amyloid β #Biophysics #Biochemistry #Medicine #Biology #Internal medicine #Cholesterol #Mathematics #Disease
paper · pdf · doi:10.1074/jbc.m706425200
openalex publication_date 2007/10/05 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/04
Apolipoprotein (apo) E is a well characterized lipid-binding protein in plasma that also exists as a common nonfibrillar component of both cerebral and systemic amyloid deposits. A genetic link between a common isoform of apoE, apoE4, and the incidence of late onset Alzheimer disease has drawn considerable attention to the potential roles of apoE in amyloid-related disease. We examined the interactions of apoE with amyloid fibrils composed of apoC-II and the amyloid-beta (Abeta) peptide. Aggregates of apoE with Abeta and apoC-II are found in Alzheimer and atherosclerotic plaques, respectively. Sedimentation velocity and fibril size distribution analysis showed that apoE3 and E4 isoforms bind and noncovalently cross-link apoC-II fibrils in a similar manner. This ability to cross-link apoC-II fibrils was abolished by the dissociation of the apoE tetramer to monomers or by thrombin cleavage to yield separate N- and C-terminal domains. Preparative ultracentrifuge binding studies indicated that apoE and the isolated N- and C-terminal domains of apoE bind with submicromolar affinities to both apoC-II and Abeta fibrils. Fluorescence quenching and resonance energy transfer experiments confirmed that both domains of apoE interact with apoC-II fibrils and demonstrated that the binding of the isolated N-terminal domain of apoE to apoC-II or Abeta fibrils is accompanied by a significant conformational change with helix three of the domain moving relative to helix one. We propose a model involving the interaction of apoE with patterns of aligned residues that could explain the general ability of apoE to bind to a diverse range of amyloid fibrils.