Structure of Triglyceride-Rich Human Low-Density Lipoproteins According to Cryoelectron Microscopy

Sherman, Michael B; Orlova, Elena V.; Decker, Glenn L.; Chiu, Wah; Pownall, Henry J.

doi:10.1021/bi0354738

Cited by 33 publications

(36 citation statements)

References 43 publications

(106 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Calculations based on LDL composition give a similar value, ∼1400 (18,19). The additive length of the longest dimension of cholesterol (∼17 Å) and an 18-carbon acyl chain (∼17 Å) is ∼34 Å, which is consistent with the X-ray scattering measurements (19).…”

Section: Resultssupporting

confidence: 76%

“…Unlike the core of normal LDL which is liquid crystalline (Fig. 3), the small, dense LDL is triglyceride-enriched and has an isotropic liquid core with no apparent striations according to cryoEM (18). Furthermore, the apo B-100 of triglyceride-rich LDL also shows impaired binding to fibroblast LDL receptors, suggesting an altered conformation (28,29).…”

Section: Resultsmentioning

confidence: 98%

See 1 more Smart Citation

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.

Self Cite

View full text Add to dashboard Cite

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 ...

show abstract

Section: Resultssupporting

confidence: 76%

Section: Resultsmentioning

confidence: 98%

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.

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, the LDL lipid core structure above the phase transition, a more physiologically relevant state, remains controversial from image evidence. Two cryo-EM studies that attempted to freeze the LDL sample from a temperature above the phase transition have reached different conclusions about the changes of the cholesterol ester packing upon the phase transition ( 15,16 ). This discrepAbstract Human LDL undergoes a reversible thermal order-disorder phase transition associated with the cholesterol ester packing in the lipid core.…”

mentioning

confidence: 99%

Human LDL core cholesterol ester packing: three-dimensional image reconstruction and SAXS simulation studies

Liu

Luo

Atkinson

2011

Journal of Lipid Research

View full text Add to dashboard Cite

This article is available online at http://www.jlr.org accumulate in the circulation as a result of a defi ciency in the LDL receptor, for example, the LDL can be oxidized and subsequentially interacts with macrophages. The accumulation of cholesterol ester transforms the macrophage into an atherogenic foam cell and contributes to the pathophysiology of atherosclerosis ( 6 ).Previous studies have shown that the cholesterol ester in the core of the LDL particle can exist in two phases accompanying change in temperature ( 7-9 ). It also has been shown that the phase transition and lipid packing may affect the rate of LDL oxidation ( 10 ). Thus, the structure of the LDL lipid core has been intensively studied to shed light on its involvement in the processes of the early atherogenic events.In the 1970s, a model for the cholesterol ester packing was proposed primarily based on X-ray and neutron scattering studies. These studies suggested that the cholesterol ester packed in concentric shells in the core at a temperature below the phase transition, and in an isotropic state at a temperature above the phase transition with the underlying assumption that the LDL is a spherical particle for both core phases ( 7-9, 11 ). More recent work from electron cryo-microscopy (cryo-EM) studies have shown in threedimensional (3D) images that the LDL particle exhibits a disk shape instead of a sphere at temperatures below the phase transition, and the cholesterol ester forms a fl at layered density ( 12-14 ) as opposed to concentric shells. However, the LDL lipid core structure above the phase transition, a more physiologically relevant state, remains controversial from image evidence. Two cryo-EM studies that attempted to freeze the LDL sample from a temperature above the phase transition have reached different conclusions about the changes of the cholesterol ester packing upon the phase transition ( 15,16 ). This discrepAbstract Human LDL undergoes a reversible thermal order-disorder phase transition associated with the cholesterol ester packing in the lipid core. Structural changes associated with this phase transition have been shown to affect the resistance of LDL to oxidation in vitro studies. Previous electron cryo-microscopy studies have provided image evidence that the cholesterol ester is packed in three fl at layers in the core at temperatures below the phase transition. To study changes in lipid packing, overall structure and particle morphology in three dimensions (3D) subsequent to the phase transition, we cryo-preserved human LDL at a temperature above phase transition (53°C) and examined the sample by electron microscopy and image reconstruction. The LDL frozen from 53°C adopted a different morphology. The central density layer was disrupted and the outer two layers formed a "disrupted shell"-shaped density, located concentrically underneath the surface density of the LDL particle. LDL is a micro emulsion that transports lipid, mainly cholesterol ester, from liver to the peripheral tissues ( 1, 2 ). LDL particles ar...

show abstract

“…An ordered three-layer internal lamellar structure with a distance of about 3.6. nm between the single lamellae was reported [32], in agreement with repeat distances derived from X-ray scattering patterns for LDL below the transition temperature. While these images were observed for LDL particles being in the liquid crystalline phase before snap-freezing, diverse results were reported for LDL particles frozen from a state above the phase transition temperature [42,43]. One plausible explanation for these discrepancies might be that the melting rate of the core lipids proceeds extremely fast.…”

Section: Core Lipid Packing and Lipid Phase Transitionmentioning

confidence: 87%