Evolutionary and structural constraints influencing apolipoprotein A-I amyloid behavior

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Dynamics

Background:

• Apolipoprotein A-I (apoA-I) is vital for reverse cholesterol transport.
• Mutations in apoA-I can cause hereditary amyloidosis due to protein aggregation.
• The link between evolutionary features, structural properties, and apoA-I amyloidogenesis is not well understood.

Purpose of the Study:

• To investigate the evolutionary conservation and pathogenic role of aggregation-prone regions (APRs) in apoA-I.
• To analyze the structural and thermodynamic impact of apoA-I mutations linked to amyloid pathology.

Main Methods:

• Combined evolutionary sequence analysis, in silico mutagenesis, and molecular dynamics (MD) simulations.
• Utilized FoldX engine for stability analysis.
• Compared pathogenic variants with silent variants from the gnomAD database.

Main Results:

• Only two of four identified amyloidogenic regions in human apoA-I (APR1 and APR4) are conserved across Sarcopterygii species.
• APR1 significantly contributes to the marginal stability of apoA-I.
• Amyloid mutations cause a greater destabilizing effect than silent variants, leading to the exposure of APR1.

Conclusions:

• APR1 is critical for maintaining the structural integrity of apoA-I.
• Destabilization of apoA-I by amyloid variants exposes APR1, potentially initiating aggregation.
• Understanding these evolutionary and structural factors provides insight into apoA-I-related amyloid diseases.