Abstract
Apolipoprotein A-I (apoA-I) plays important structural and functional roles in plasma high density lipoprotein (HDL) that is responsible for reverse cholesterol transport. However, a molecular understanding of HDL assembly and function remains enigmatic. The 2.2-Å crystal structure of Δ(185-243)apoA-I reported here shows that it forms a half-circle dimer. The backbone of the dimer consists of two elongated antiparallel proline-kinked helices (five AB tandem repeats). The N-terminal domain of each molecule forms a four-helix bundle with the helical C-terminal region of the symmetry-related partner. The central region forms a flexible domain with two antiparallel helices connecting the bundles at each end. The two-domain dimer structure based on helical repeats suggests the role of apoA-I in the formation of discoidal HDL particles. Furthermore, the structure suggests the possible interaction with lecithin-cholesterol acyltransferase and may shed light on the molecular details of the effect of the Milano, Paris, and Fin mutations.
Highlights
With a semicircular backbone formed from antiparallel helical repeats, the structure allows us to model the formation of discoidal high density lipoprotein (HDL) particles with different geometries
In addition to forming a helix bundle to cover the hydrophobic surface, it contributes Trp8 and Phe33 to aromatic clusters at each end of the helix bundle that stabilizes the bundle. It forms two -cation interactions with H1 that hold the extended segment of the first B repeat of H1 in place
Unhinging of the bundle can occur at the loop between the short helical second B sequence of H1 and the first A repeat of H2 (Gly65, Pro66, Val67, and Thr68) and at the top of the bundle at the short helical segment at right angles to the bundle axis (Ala37–Gln41)
Summary
The structure shows the molecular details of the stabilization of lipid-free apoA-I by the N-terminal exon-3-encoded residues and suggests the role of dimerization in the assembly of HDL. Central Segment Hinge—The H5(AB3) region of opposing monomers forms two antiparallel helices connecting the helix bundles at each end (Fig. 2).
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