Deficiency Mutations of Alpha-1 Antitrypsin. Effects on Folding, Function, and Polymerization

Area of Science:

• Biochemistry
• Genetics
• Molecular Biology

Background:

• Alpha-1 antitrypsin deficiency (AATD) is linked to misfolding, polymerization, and impaired secretion of alpha-1 antitrypsin (AAT).
• This leads to severe liver and lung diseases.
• Understanding AAT variants is crucial for managing AATD.

Observation:

• A novel Ala336Pro AAT deficiency variant was identified in a homozygous individual.
• This variant presented a unique biochemical phenotype with moderate deficiency levels but significant polymerization.
• The protein existed mainly as inactive polymer with reduced monomer activity.

Findings:

• Ala336Pro AAT readily populates polymerogenic intermediates, leading to increased polymerization compared to wild-type and Z variants.
• Folding is less impaired in Ala336Pro AAT than in the Z variant.
• Folding efficiency does not directly correlate with polymerization tendency, differentiating generalized misfolding from polymerization in AAT variants.

Implications:

• The Ala336Pro variant causes functional deficiency comparable to ZZ homozygotes.
• Findings suggest distinct roles for the 'breach' and 'shutter' regions of strand 5A in AAT folding and polymerization.
• Quantifying loss-of-function is essential for individualized patient care in AATD.