Wong-Mauldin K, Raussens V, Forte TM, Ryan RO
Apolipoprotein A-V N-terminal domain altered lipid interaction properties in vitro explain hypertriglyceridemic phenotype associated with natural truncation mutants. [JOURNAL ARTICLE]
J Biol Chem 2009 Oct 13.
The N-terminal 146 residues of apolipoprotein (apo) A-V adopt a helix bundle conformation in the absence of lipid. Since similar sized truncation mutants in human subjects correlate with severe hypertriglyceridemia (HTG), the lipid binding properties of apoA-V(1-146) were studied. Upon incubation with phospholipid in vitro, apoA-V(1-146) forms reconstituted high density lipoproteins 15 - 17 nm in diameter. Far UV circular dichroism spectroscopy analyses of lipid bound apoA-V(1-146) yielded an alpha-helix secondary structure content of 60%. Fourier transformed infrared spectroscopy analysis revealed that apoA-V(1-146) alpha-helix segments align perpendicular with respect to particle phospholipid fatty acyl chains. Fluorescence spectroscopy of single Trp variant apoA-V(1-146) indicate lipid interaction is accompanied by a conformational change. The data are consistent with a model wherein apoA-V(1-146) alpha-helices circumscribe the perimeter of a disk-shaped bilayer. The ability of apoA-V(1-146) to solubilize dimyristoylphosphatidylcholine vesicles at a rate faster than full-length apoA-V suggests N- and C-terminal interactions in the full-length protein modulate its lipid binding properties. Preferential association of apoA-V(1-146) with murine plasma HDL, but not with VLDL, suggests particle size is a determinant of its lipoprotein binding specificity. It may be concluded that defective lipoprotein binding of truncated apoA-V contributes to the HTG phenotype associated with truncation mutations in human subjects.
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