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Updated: May 7, 2026

Purification and Aggregation of the Amyloid Precursor Protein Intracellular Domain
10:08

Purification and Aggregation of the Amyloid Precursor Protein Intracellular Domain

Published on: August 28, 2012

Structural basis for distinct functions of the naturally occurring Cys mutants of human apolipoprotein A-I

Olga Gursky1, Martin K Jones, Xiaohu Mei

  • 1Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118.

Journal of Lipid Research
|September 17, 2013
PubMed

Insights

Structural models reveal how specific mutations in apolipoprotein A-I (ApoA-I) alter its conformation on high-density lipoprotein (HDL). These changes explain the enhanced cardioprotection observed in ApoA-I mutants despite lower HDL levels.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Cardiovascular Science

Background:

  • High-density lipoprotein (HDL) plays a crucial role in reverse cholesterol transport and atherosclerosis prevention.
  • Apolipoprotein A-I (ApoA-I) is the primary protein component of HDL, providing structural integrity and functional activity.
  • Specific ApoA-I mutations, like ApoA-I(Milano) and ApoA-I(Paris), confer significant cardioprotection despite altered HDL levels.

Purpose of the Study:

  • To propose detailed structural models for ApoA-I(Milano) and ApoA-I(Paris) mutants bound to HDL.
  • To elucidate how intermolecular disulfide bonds in these mutants influence ApoA-I conformation.
  • To understand the functional implications of these conformational changes on HDL's role in lipid metabolism.

Main Methods:

  • Modification of existing ApoA-I conformational ensembles on HDL.
  • Incorporation of structural constraints from intermolecular disulfides involving cysteine residues (C173 and C151).
  • Molecular dynamics simulations of ApoA-I(Milano) homodimers and comparison with experimental data.

Main Results:

  • Proposed models show modified double-belt conformations due to belt rotation, main-chain unhinging, and Pro-induced helical bending.
  • Molecular termini of ApoA-I repack on HDL, with conserved packing around specific helices (helix-5, -6, or -7) depending on the mutant.
  • Disulfide-induced constraints alter ApoA-I conformation, facilitating C-terminal dissociation and enhanced lipid recruitment.

Conclusions:

  • The structural models provide a unified explanation for previous findings on ApoA-I(Milano).
  • Mutational effects propagate to the molecular termini, altering ApoA-I conformation, dynamics, and function.
  • These findings offer insights into the mechanism of enhanced cardioprotection by specific ApoA-I variants.

Keywords:
Milano and Paris mutationsatherosclerosisdouble-belt and trefoil/tetrafoil conformationsprotein dynamics and functionprotein-lipid interactions

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