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Purification and Aggregation of the Amyloid Precursor Protein Intracellular Domain
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Purification and Aggregation of the Amyloid Precursor Protein Intracellular Domain

Published on: August 28, 2012

The fibrillogenic L178H variant of apolipoprotein A-I forms helical fibrils

Jitka Petrlova1, Trang Duong2, Megan C Cochran2

  • 1Department of Experimental Medical Sciences, Lund University, S-221 84 Lund, Sweden; and.

Journal of Lipid Research
|December 21, 2011
PubMed

Insights

The apolipoprotein A-I (apoA-I) L178H variant forms distinct amyloid fibrils with increased helical structure, contributing to tissue-specific protein deposition. This highlights apoA-I

Area of Science:

  • Biochemistry and Molecular Biology
  • Structural Biology
  • Protein Misfolding Diseases

Background:

  • Amyloidogenic variants of apolipoprotein A-I (apoA-I) are linked to various protein deposition diseases.
  • Previous studies showed the G26R apoA-I variant forms fibrils and causes renal/hepatic accumulation.
  • Mutations in different apoA-I regions (N-terminal vs. residues 170-178) result in distinct tissue deposition patterns.

Purpose of the Study:

  • To investigate the structural changes and fibril formation of the apoA-I L178H variant.
  • To compare the fibrillogenic properties of L178H with the previously studied G26R variant.
  • To understand how apoA-I structural dynamics contribute to tissue-specific amyloid deposition.

Main Methods:

  • Characterization of the initial structure, stability, and lipid binding of the L178H mutant.
  • Incubation of L178H at 37°C to monitor structural changes over time using spectroscopic methods.
  • Analysis of fibril morphology (diameter, length) formed by the L178H mutant upon prolonged incubation.

Main Results:

  • The L178H variant exhibits altered tertiary conformation, decreased stability, and modified lipid binding compared to wild-type apoA-I.
  • Unlike G26R, L178H shows an increase in helical structure upon incubation (t(1/2) ≈ 12 days).
  • L178H forms amyloid fibrils (10 nm diameter, 30-120 nm length) after prolonged incubation.

Conclusions:

  • ApoA-I possesses the capacity to adopt multiple fibrillar conformations.
  • The L178H variant's structural changes and fibril formation mechanism differ from the G26R variant.
  • The dynamic nature of apoA-I and its resulting conformations likely influence tissue-specific protein deposition in amyloidosis.

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