Molecular basis of exchangeable apolipoprotein function

Narayanaswami, Vasanthy; Ryan, Robert O.

doi:10.1016/s1388-1981(99)00176-6

Cited by 158 publications

(170 citation statements)

References 117 publications

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confidence: 99%

“…[11][12][13][14][15]. Physiologically, a lipid-free form of apoA-I exists in a thermodynamically labile state but is rapidly lipidated, resulting in nearly all of the apoA-I in vivo being lipid-bound (11)(12)(13)16). However, evidence is accumulating on lipid-free͞poor apoA-I being the primary acceptor of FC from peripheral cells (16) and as the substrate for myeloperoxidase-mediated chlorination, which impairs ABCA1-mediated cholesterol efflux (17).…”

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confidence: 99%

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RETRACTED: Crystal structure of human apolipoprotein A-I: Insights into its protective effect against cardiovascular diseases

Ajees

Anantharamaiah

Mishra

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

201

200

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Despite three decades of extensive studies on human apolipoprotein A-I (apoA-I), the major protein component in high-density lipoproteins, the molecular basis for its antiatherogenic function is elusive, in part because of lack of a structure of the full-length protein. We describe here the crystal structure of lipid-free apoA-I at 2.4 Å. The structure shows that apoA-I is comprised of an N-terminal four-helix bundle and two C-terminal helices. The N-terminal domain plays a prominent role in maintaining its lipid-free conformation, indicating that mutants with truncations in this region form inadequate models for explaining functional properties of apoA-I. A model for transformation of the lipid-free conformation to the high-density lipoprotein-bound form follows from an analysis of solvent-accessible hydrophobic patches on the surface of the structure and their proximity to the hydrophobic core of the four-helix bundle. The crystal structure of human apoA-I displays a hitherto-unobserved array of positively and negatively charged areas on the surface. Positioning of the charged surface patches relative to hydrophobic regions near the C terminus of the protein offers insights into its interaction with cell-surface components of the reverse cholesterol transport pathway and antiatherogenic properties of this protein. This structure provides a much-needed structural template for exploration of molecular mechanisms by which human apoA-I ameliorates atherosclerosis and inflammatory diseases.

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confidence: 99%

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confidence: 99%

RETRACTED: Crystal structure of human apolipoprotein A-I: Insights into its protective effect against cardiovascular diseases

Ajees

Anantharamaiah

Mishra

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

201

200

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“…In the case of human apoA-I or insect apolipophorin III (27), it has been proposed that lipid interaction is facilitated by adoption of a loosely folded conformation in buffer. Secondary structure elements in both these proteins are stabilized by lipid association, and this may represent a driving force for their intrinsic lipid surface seeking property.…”

Section: Discussionmentioning

confidence: 99%

Structure−Function Studies of Human Apolipoprotein A-V: A Regulator of Plasma Lipid Homeostasis

et al. 2003

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To investigate structure and function relations of a new member of the exchangeable apolipoprotein family that modulates plasma lipid levels, recombinant human apolipoprotein (apo) A-V was produced in Escherichia coli and isolated by a combination of nickel chelation affinity chromatography and reversed-phase HPLC. Antibodies directed against apoA-V were generated and employed in immunoblotting experiments. Anti-apoA-V IgG gave a strong response against recombinant apoA-V from E. coli and human apoA-V expressed in transgenic mice, but did not recognize human apoA-I or apoA-IV. In neutral-pH buffers, at concentrations of >0.1 mg/mL, isolated lipid-free apoA-V is poorly soluble. By contrast, apoA-V is soluble in 50 mM sodium citrate (pH 3.0). Far-UV circular dichroism analysis and spectral deconvolution reveal that apoA-V possesses 32% α-helix, 33% β-sheet, 16% β-turn, and 18% random coil secondary structure conformers. Temperature-induced denaturation studies gave rise to a transition midpoint of 47.1 °C. Upon being cooled to ambient temperature from 85 °C, apoA-V failed to recover all of the negative ellipticity present in unheated apoA-V. ApoA-V interacts with bilayer vesicles of dimyristoylphosphatidylcholine to form discoidal complexes with diameters in the range of 15−20 nm. However, apoA-V was a poor activator of lecithin:cholesterol acyltransferase where the activity was 8.5 ± 1.8% of that of apoA-I. Furthermore, apoA-V failed to support enhanced efflux of cholesterol from cAMP-treated J774 macrophages, although low levels of efflux were obtained from unstimulated cells. Taken together, the results demonstrate recombinant apoA-V possesses unique structural and functional characteristics, in keeping with its proposed role in the modulation of plasma lipid levels.

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“…Macrophages-ApoE is a ligand for LDL receptor, LRP and VLDL receptor, and binds to cell surface HSPGs (31,42). Within atherosclerotic lesions, lipoproteins have been found to contain apoE in addition to apoB-100 (43,44).…”

Section: Effects Of Apoe and Lpl On Emulsion Uptake By J774mentioning

confidence: 99%

Ceramide in Lipid Particles Enhances Heparan Sulfate Proteoglycan and Low Density Lipoprotein Receptor-related Protein-mediated Uptake by Macrophages

Morita

Kawabe

Sakurai

et al. 2004

Journal of Biological Chemistry

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Arterial wall sphingomyelinase (SMase) has been proposed to be involved in atherogenesis. SMase modification of lipoproteins has been shown to occur in atherosclerotic lesions and to facilitate their uptake by macrophages and foam cell formation. To investigate the mechanism of macrophage uptake enhanced by SMase, we prepared lipid emulsions containing sphingomyelin (SM) or ceramide (CER) as model particles of lipoproteins. SMase remarkably increased the uptake of SM-containing emulsions by J774 macrophages without apolipoproteins. The emulsion uptake was negatively correlated with the degree of particle aggregation by pretreatment with SMase, whereas the uptake of CERcontaining emulsions was significantly larger than SMcontaining emulsions, indicating that enhancement of uptake is due to the generation of CER molecules in particles but not to the aggregation by SMase. Heparan sulfate proteoglycans (HSPGs) and low density lipoprotein receptor-related protein (LRP) were crucial for CER-enhanced emulsion uptake, because heparin or lactoferrin inhibited the emulsion uptake. Confocal microscopy also showed that SMase promoted both binding and internalization of emulsions by J774 macrophages, which were almost abolished by lactoferrin. Apolipoprotein E further increased the uptake of CERcontaining emulsions compared with SM-containing emulsions. These findings suggest the generation of CER in lipoproteins by SMase facilitates the macrophage uptake via HSPG and LRP pathways and plays a crucial role in foam cell formation. Thus, CER may act as an important atherogenic molecule.

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Molecular basis of exchangeable apolipoprotein function

Cited by 158 publications

References 117 publications

RETRACTED: Crystal structure of human apolipoprotein A-I: Insights into its protective effect against cardiovascular diseases

RETRACTED: Crystal structure of human apolipoprotein A-I: Insights into its protective effect against cardiovascular diseases

Structure−Function Studies of Human Apolipoprotein A-V: A Regulator of Plasma Lipid Homeostasis

Ceramide in Lipid Particles Enhances Heparan Sulfate Proteoglycan and Low Density Lipoprotein Receptor-related Protein-mediated Uptake by Macrophages

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