Figure 1. Model representation of apoA-I structure.

(A) Cartoon showing apoA-I and HDL. Each HDL particle contains 2–5 copies of apoA-I and polar lipids (mainly phospholipids and cholesterol) on the surface, and apolar lipids (mainly cholesterol ester and triacylglycerol) in the core. ApoA-I on HDL adopts an antiparallel helical “double-belt” conformation.^5,6 ApoA-I can dissociate from HDL in a labile monomeric free form that can: i) rapidly bind to other lipoproteins or generate new HDL (^8,9 and refs. therein), ii) get degraded or iii) misfold.

(B) Amyloid “hot spots” and mutation sites mapped on the proposed structure of apoA-I monomer. The structure was obtained from the dimer observed in the 2.2 Å crystal structure of Δ(185–243)apoA-I (PDB ID 3R2P) via the domain swapping of helix IV residues 143–184 around the dimer 2-fold (circular arrow).⁷ The flexible C-terminal tail (residues 185–243, drawn by line) was absent from the crystallized construct. Disease-causing point substitutions explored in the current study are indicated. Residue segments that were proposed to be important for amyloidosis are indicated: 14–22 (blue) is the major predicted amyloid “hot spot”; 53–58 (teal) and 69–72 (yellow) are weakly predicted amyloid “hot spots”; 44–55 is the sole β-strand-like segment in the crystal structure; 83–93 contain the cleavage sites generating 1–83 to 1–93 fragments found in AApoAI deposits; and 227–232 (red) is the predicted C-terminal amyloid “hot spot”.^21–25 The latter segment overlaps the α-helix forming the primary lipid binding site.