Hot spots in apolipoprotein A-II misfolding and amyloidosis in mice and men

Area of Science:

• Biochemistry
• Molecular Biology
• Protein Misfolding Diseases

Background:

• Apolipoprotein A-II (ApoA-II) is a major component of high-density lipoproteins.
• Misfolding of ApoA-II, particularly with C-terminal extensions in humans or point mutations in mice, can lead to amyloidosis.
• The precise molecular mechanisms driving ApoA-II misfolding from its native alpha-helical structure to amyloidogenic cross-beta-sheet structures remain unclear.

Purpose of the Study:

• To elucidate the molecular mechanism of apolipoprotein A-II (ApoA-II) misfolding and amyloid formation.
• To identify specific regions within ApoA-II that initiate the aggregation process.
• To explain the differential propensity for amyloidosis between human and murine ApoA-II.

Main Methods:

• Utilized 12 distinct sequence-based prediction algorithms to analyze the ApoA-II sequence.
• Identified two ten-residue segments predicted to initiate beta-aggregation.
• Integrated bioinformatics predictions with existing experimental data on ApoA-II fragments.

Main Results:

• Identified two specific ten-residue segments within ApoA-II as probable initiators of beta-aggregation.
• Bioinformatic predictions were experimentally validated by previous studies on ApoA-II fragments.
• The findings explain the amyloidogenic potential of human ApoA-II's C-terminal extension.

Conclusions:

• The study successfully identified key segments responsible for ApoA-II beta-aggregation.
• These findings provide a molecular basis for understanding ApoA-II-related amyloidosis.
• The results reconcile the high intrinsic aggregation propensity of human ApoA-II with its usual lack of amyloidosis, except when mutations occur.