Relevance of the amino acid conversions L144R (Zaragoza) and L159P (Zavalla) in the Apolipoprotein A-I binding site for Haptoglobin

The HDL ApolipoproteinA-I (ApoA-I) stimulates the enzyme LCAT in the reverse cholesterol transport pathway. Two ApoA-I variants, Zaragoza (L144R) and Zavalla (L159P), are associated with low levels of HDL-cholesterol though normal LCAT activity. Haptoglobin interacts with ApoA-I, impairing LCAT stimulation. Synthetic peptides, matching the haptoglobin-binding site of native or variant ApoA-I (native: P2a; variants: Zav-pep and Zar-pep), bound haptoglobin with different activity: Zar-pep>P2a>Zav-pep. They also differently rescued LCAT in vitro activity in presence of haptoglobin (P2a = Zar-pep>Zav-pep). Therefore both amino acid conversions affect haptoglobin binding and LCAT regulation. We highlight the role of haptoglobin for LCAT regulation in subjects with ApoA-I variants.