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Jens Lagerstedt

Associate professor

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Mapping the structural transition in an amyloidogenic apolipoprotein A-I

Author

  • Jens O Lagerstedt
  • Giorgio Cavigiolio
  • Linda M Roberts
  • Hyun-Seok Hong
  • Lee-Way Jin
  • Paul G Fitzgerald
  • Michael N. Oda
  • John C Voss

Summary, in English

The single amino acid mutation G26R in human apolipoprotein A-I (apoA-IIOWA) leads to the formation of beta-secondary structure rich amyloid fibrils in vivo. Here we show that full-length apoA-IIOWA has a decreased lipid-binding capability, an increased amino-terminal sensitivity to protease, and a propensity to form annular protofibrils visible by electron microscopy. The molecular basis for the conversion of apolipoprotein A-I to a proamyloidogenic form was examined by electron paramagnetic resonance spectroscopy. Our recent findings [Lagerstedt, J. O., Budamagunta, M. S., Oda, M. N., and Voss, J. C. (2007) J. Biol. Chem. 282, 9143-9149] indicate that Gly26 in the native apoprotein separates a preceding beta-strand structure (residues 20-25) from a downstream largely alpha-helical region. The current study demonstrates that the G26R variant promotes a structural transition of positions 27-56 to a mixture of coil and beta-strand secondary structure. Microscopy and staining by amyloidophilic dyes suggest that this alteration extends throughout the protein within 1 week of incubation in vitro, leading to insoluble aggregates of distinct morphology. The severe consequences of the Iowa mutation likely arise from the combination of losing the contribution of the native Gly residue in terminating beta-strand propagation and the promotion of beta-structure when an Arg is introduced adjacent to the succeeding residue of identical charge and size, Arg27.

Publishing year

2007-08-28

Language

English

Pages

9-9693

Publication/Series

Biochemistry

Volume

46

Issue

34

Document type

Journal article

Publisher

The American Chemical Society (ACS)

Keywords

  • Apolipoprotein A-I
  • Circular Dichroism
  • Electron Spin Resonance Spectroscopy
  • Humans
  • Models, Molecular
  • Peptide Fragments
  • Phospholipids
  • Protein Conformation
  • Spectroscopy, Fourier Transform Infrared
  • Thiazoles
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Status

Published

ISBN/ISSN/Other

  • ISSN: 0006-2960