Conformational and aggregation properties of the 1-93 fragment of apolipoprotein A-I

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Abstract

Several disease-linked mutations of apolipoprotein A-I, the major protein in high-density lipoprotein (HDL), are known to be amyloidogenic, and the fibrils often contain N-terminal fragments of the protein. Here, we present a combined computational and experimental study of the fibril-associated disordered 1-93 fragment of this protein, in wild-type and mutated (G26R, S36A, K40L, W50R) forms. In atomic-level Monte Carlo simulations of the free monomer, validated by circular dichroism spectroscopy, we observe changes in the position-dependent β-strand probability induced by mutations. We find that these conformational shifts match well with the effects of these mutations in thioflavin T fluorescence and transmission electron microscopy experiments. Together, our results point to molecular mechanisms that may have a key role in disease-linked aggregation of apolipoprotein A-I.

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Subject classification (UKÄ) – MANDATORY

  • Other Physics Topics
  • Biophysics
  • Physical Chemistry

Keywords

  • Amyloid, Apolipoprotein A-I, Circular Dichroism, Intrinsically Disordered Proteins, Molecular Dynamics Simulation, Protein Structure, Secondary
Original languageEnglish
Pages (from-to)1559-71
Number of pages13
JournalProtein Science
Volume23
Issue number11
Publication statusPublished - 2014 Nov
Publication categoryResearch
Peer-reviewedYes