Thermal Transitions in Human Plasma Low Density Lipoproteins

Deckelbaum, R.J.; Shipley, G. Graham; Small, D M; Rs, Lees; George, P M

doi:10.1126/science.170681

Cited by 204 publications

(135 citation statements)

References 15 publications

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“…4A left face) that are potential sites where enzymes and lipid transfer proteins could interact with the phospholipid surface via their putative interfacial recognition sites. The most notable of these is cholesteryl ester transfer protein, which transports CE from HDL to LDL and very lowdensity lipoprotein (VLDL), and is known to bind to phospholipid surfaces that contain no protein (23).…”

Section: Resultsmentioning

confidence: 99%

“…the α-helix rich and β-sheet rich domains by considering: (i) the unusual structural motifs of apo B-100 with several unusually long α helices in the two α-helix rich domains, (ii) the consensus that the apo B-100 is distributed throughout the surface of the particle (5,7,9), and lastly (iii) the scattering density difference between protein and lipids, (Fig. 4 B, C).…”

Section: Resultsmentioning

confidence: 99%

“…LDL exhibits a thermal liquid crystalline-to-isotropic transition of its cholesteryl esters (CEs) between 25 and 35°C (5). Although several models of LDL attempt to integrate its structure and biology (5-9), a reliable three-dimensional structure of LDL or the LDL · LDLr complex has not yet been reported.…”

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confidence: 99%

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Model of human low-density lipoprotein and bound receptor based on CryoEM

Ren

Rudenko

Ludtke³

et al. 2009

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

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Human plasma low-density lipoproteins (LDL), a risk factor for cardiovascular disease, transfer cholesterol from plasma to liver cells via the LDL receptor (LDLr). Here, we report the structures of LDL and its complex with the LDL receptor extracellular domain (LDL · LDLr) at extracellular pH determined by cryoEM. Difference imaging between LDL · LDLr and LDL localizes the site of LDLr bound to its ligand. The structural features revealed from the cryoEM map lead to a juxtaposed stacking model of cholesteryl esters (CEs). High density in the outer shell identifies protein-rich regions that can be accounted for by a single apolipoprotein (apo B-100, 500 kDa) leading to a model for the distribution of its α-helix and β-sheet rich domains across the surface. The structural relationship between the apo B-100 and CEs appears to dictate the structural stability and function of normal LDL.apolipoprotein B-100 | cholesteryl ester | electron cryomicroscopy | LDL receptor Low-density lipoproteins (LDL), which are heterogeneous with respect to composition, shape, size, density, and charge (1, 2), are the major carriers of cholesterol in human plasma. LDL is removed from plasma by hepatic LDL receptors (LDLr), which maintain cholesterol homeostasis (3). LDLr variants with impaired binding to LDL cause familial hypercholesterolemia that leads to premature atherosclerotic coronary artery disease in affected patients (4). The extracellular domain of LDLr binds to LDL via apo B-100, a 4,536 amino acid polypeptide, after which the complex (LDL · LDLr) undergoes endocytosis, lysosomal degradation of LDL, and receptor recycling to the cell surface (1,3,4). Thus, interactions between LDL and LDLr are integral to the cholesterol homeostasis that regulates plasma LDL levels.LDL exhibits a thermal liquid crystalline-to-isotropic transition of its cholesteryl esters (CEs) between 25 and 35°C (5). Although several models of LDL attempt to integrate its structure and biology (5-9), a reliable three-dimensional structure of LDL or the LDL · LDLr complex has not yet been reported. Herein, we present a model of LDL and the complex, LDL · LDLr, of LDL-bound LDL receptor extracellular domain (1-699 a.a.) at extracellular pH determined by electron cryomicroscopy (cryoEM), a technique that preserves the native structure of the particles. Result and DiscussionCryoEM micrographs of LDL embedded in vitreous ice contain spherical, ellipsoidal, and discoidal particles with internal striations (Fig. 1A and B). Since the LDL preparation is heterogeneous, our reconstruction was computed from ∼8; 500 particle images of LDL particles that were computationally selected from an original pool over ∼48; 000 particle images. The convergence of the structure from this subpopulation of particle images provides a statistically defined and robust density map displaying the most prominent and reliable structural features of LDL (Fig. 1C, and Figs. S1, 2). The reconstructed LDL subpopulation is approximately a flattened ellipsoid with planar opposing faces (∼250 Å ...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Model of human low-density lipoprotein and bound receptor based on CryoEM

Ren

Rudenko

Ludtke³

et al. 2009

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

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“…Since the lipid component of LDL is emphasized in the neutron data, a temperature series between 10'C and 50 C over the complete Q range to 3.3 nm-' was studied in order to identify the phase transition in the LDL core from a liquid crystalline state at low temperature to a more disordered state [44]. A maximum was seen at Q = 1.6 n n -' at 10'C and at 20"C, which was replaced at 37°C and 50°C by another one seen at Q = 0.9 nm-'.…”

Section: Nutive Ldlmentioning

confidence: 99%

Structural changes in oxidised low‐density lipoproteins and of the effect of the anti‐atherosclerotic drug probucol observed by synchrotron X‐ray and neutron solution scattering

Bellamy

Nealis

Aitken

et al. 1989

European Journal of Biochemistry

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The atherosclerotic properties of low-density lipoproteins (LDL) are thought to be strongly enhanced by oxidation. The lipid-lowering drug probucol reduces the susceptibility of LDL to oxidation. Synchrotron X-ray and high-flux neutron solution scattering curves were used to characterise the structural properties of human LDL, before and after modification by oxidation with CuZt and the addition of probucol, in order to evaluate these techniques. Analyses based on Guinier plots, simple two-shell spherical modelling, and the use of cubic splines and indirect transformation show that a 20-h incubation with Cu2+ ions (but not 6 h) causes some of the LDL to associate to form larger aggregated particles. Gel electrophoresis on Cu2+-oxidised LDL shows a concomitant degradation of the apolipoprotein B-100 as well as the formation of high molecular mass forms. These experiments indicate that the apoprotein B-100 structure has been significantly disrupted by oxidation. The addition of probucol to LDL causes an increase in the polydispersity of LDL, as evidenced by small changes in the Guinier curves and some weakening of the minima in the X-ray scattering curves. N o changes in the quasispherical shape of LDL are observed and gel electrophoresis indicates no changes. It is possible that probucol may exert its effect by increasing the range of sizes of LDL and that the lipid-lowering effect of probucol in vivo might be caused by the preferential catabolism of the higher molecular mass forms of LDL thus created.Cardiovascular disease is implicated in half of all deaths in industrialised countries. Epidemiological studies show a strong positive correlation between elevated plasma concentrations of low-density lipoproteins (LDL) cholesterol and the risk of premature coronary heart disease [l, 21. The role of LDL is to deliver cholesterol to body tissues which require it for membrane synthesis and steroid hormone production [3]. LDL is distinguishable from all other lipoprotein classes in plasma by its high relative proportion of cholesteryl ester and the presence of a single apolipoprotein (apo) B-100. LDL has a simple quasi-spherical particle symmetry of outer diameter 21 -25 nm, as determined by electron microscopy and solution scattering [4 -81. It is composed of one molecule of apo B-100 with a 4% (by mass) oligosaccharide content (Table 1) and its binding to lipid can be likened to its insertion into a lipid vesicle [8 -121. Compositional studies show that LDL is 77% (by mass) lipid. There are about 2900 lipid molecules (Table l), primarily cholesteryl linoleate and triacylglycerol in the core, surrounded by a monolayer of polar phospholipids and cholesterol. Secondary structure predictions, circular dichroism and Fourier-transform infrared (FT-IR) spectroscopy show that apo B-100 is approximately 40% cc-helix, 25% fl-sheet and 35% random coil in its main chain conformation [9, 11, 13 - B-100 are found at the N-terminus, this part is presumed to constitute a globular structure.The presence of lipid-laden foam cells is a...

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“…Although little is known about the effects of triacylglycerols in membranes, studies have already shown that the triacylglycerols have the effect of disordering the molecular organization of membrane cholesteryl ester and probably altering the lipid composition of the plasma membrane (Deckelbaum et al, 1977;Tall et al, 1978).…”

Section: Discussionmentioning

confidence: 99%

Lauric acid inhibits the maturation of vesicular stomatitis virus

Hornung

Amtmann

Sauer

1994

Journal of General Virology

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In the presence of lauric acid (C12), the production of infectious vesicular stomatitis virus (VSV) was inhibited in a dose-dependent manner. The inhibitory effect was reversible: after removal of C12 the antiviral effect disappeared. In addition, the chain length of the monocarboxylic acids proved to be crucial, as those with shorter or longer chains were less effective or had no antiviral activity. Concomitant with the C12-induced inhibition was the stimulation of triacylglycerol synthesis, increasing the amount up to ninefold. Analysis of the antiviral mechanism of C 12 revealed that the correct assembly of the viral components was disturbed, but viral RNA and protein synthesis remained unimpaired.By cell fractionation and Western blot analysis the amount of viral M protein located in the plasma membrane was found to be markedly reduced after treatment with C12, whereas in the cytoplasm the quantity of M protein was similar to that in untreated cells. C12 did not influence M protein synthesis, but prevented the binding of M protein to the host cell membrane, where the protein plays an essential role in virus assembly. Thus, treatment of VSV-infected cells with C12 resulted in inhibition of virus release. It is suggested that the newly synthesized triacylglycerols might interact with the host cell plasma membrane and interfere with virus maturation.

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Thermal Transitions in Human Plasma Low Density Lipoproteins

Cited by 204 publications

References 15 publications

Model of human low-density lipoprotein and bound receptor based on CryoEM

Model of human low-density lipoprotein and bound receptor based on CryoEM

Structural changes in oxidised low‐density lipoproteins and of the effect of the anti‐atherosclerotic drug probucol observed by synchrotron X‐ray and neutron solution scattering

Lauric acid inhibits the maturation of vesicular stomatitis virus

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