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Secondary structure changes in ApoA-I Milano (R173C) are not accompanied by a decrease in protein stability or

Jitka Petrlova1, Jonathan Dalla-Riva1, Matthias Mörgelin2

  • 1Department of Experimental Medical Science, Lund University, Lund, Sweden.

Plos One
|April 24, 2014
PubMed

Insights

The Milano variant of apolipoprotein A-I (apoA-I), despite structural changes, does not form amyloid fibrils. This suggests that certain apoA-I mutations may protect against cardiovascular disease by preventing fibril formation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cardiovascular Research

Background:

  • Apolipoprotein A-I (apoA-I) is crucial for reverse cholesterol transport via high-density lipoprotein (HDL).
  • Specific apoA-I variants are linked to hereditary amyloidosis and altered protein stability.
  • Previous studies identified G26R and L178H apoA-I variants with reduced stability and increased fibril formation.

Purpose of the Study:

  • To investigate the fibrillogenic potential of the apoAI-Milano (apoAI-M) variant (R173C).
  • To understand the structural and functional implications of the R173C substitution in apoA-I.
  • To correlate apoAI-M properties with its association with low cardiovascular disease prevalence in carriers.

Main Methods:

  • Biochemical analysis of apoAI-M stability and secondary structure.
  • Thioflavin T (ThT) binding assays to assess fibril formation.
  • Transmission electron microscopy (TEM) to visualize protein aggregates.
  • Comparison with known fibrillogenic variants like L178H.

Main Results:

  • ApoAI-M exhibited increased helical content, similar to the fibrillogenic L178H variant.
  • Low Thioflavin T binding was observed for apoAI-M during prolonged incubation.
  • Electron microscopy confirmed the absence of fibril formation for the apoAI-M variant.
  • Despite shared features with fibrillogenic variants, apoAI-M did not form amyloid fibrils.

Conclusions:

  • The apoAI-M (R173C) mutation does not induce apoA-I fibril formation.
  • Secondary structural changes in apoA-I may be protective if they do not lead to amyloidogenesis.
  • This finding offers insights into the protective effects of certain apoA-I variants against cardiovascular disease.

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