title: Conservation of apolipoprotein A-I's central domain structural elements upon lipid association on different high-density lipoprotein subclasses.
abstract: The antiatherogenic properties of apolipoprotein A-I (apoA-I) are derived, in part, from lipidation-state-dependent structural elements that manifest at different stages of apoA-I's progression from lipid-free protein to spherical high-density lipoprotein (HDL). Previously, we reported the structure of apoA-I's N-terminus on reconstituted HDLs (rHDLs) of different sizes. We have now investigated at the single-residue level the conformational adaptations of three regions in the central domain of apoA-I (residues 119-124, 139-144, and 164-170) upon apoA-I lipid binding and HDL formation. An important function associated with these residues of apoA-I is the activation of lecithin:cholesterol acyltransferase (LCAT), the enzyme responsible for catalyzing HDL maturation. Structural examination was performed by site-directed tryptophan fluorescence and spin-label electron paramagnetic resonance spectroscopies for both the lipid-free protein and rHDL particles 7.8, 8.4, and 9.6 nm in diameter. The two methods provide complementary information about residue side chain mobility and molecular accessibility, as well as the polarity of the local environment at the targeted positions. The modulation of these biophysical parameters yielded new insight into the importance of structural elements in the central domain of apoA-I. In particular, we determined that the loosely lipid-associated structure of residues 134-145 is conserved in all rHDL particles. Truncation of this region completely abolished LCAT activation but did not significantly affect rHDL size, reaffirming the important role of this structural element in HDL function.
authors.affiliation: Children's Hospital Oakland Research Institute , Oakland, California 94609, United States.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Oda
authors.forename: Madhu S
authors.initials: MS
authors.lastname: Budamagunta
authors.forename: Ethan G
authors.initials: EG
authors.lastname: Geier
authors.forename: Sajiv H
authors.initials: SH
authors.lastname: Chandradas
authors.forename: Baohai
authors.initials: B
authors.lastname: Shao
authors.forename: Jay W
authors.initials: JW
authors.lastname: Heinecke
authors.forename: John C
authors.initials: JC
authors.lastname: Voss
authors.forename: Giorgio
authors.initials: G
authors.lastname: Cavigiolio
mesh_terms: D016632:Apolipoprotein A-I / Q000737:chemistry* / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000145:classification* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000145:classification / Q000378:metabolism
chemical_list: D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D011994:Recombinant Proteins