Apolipoprotein E•dipalmitoylphosphatidylcholine particles are ellipsoidal in solution

Peters‐Libeu, Clare; Newhouse, Yvonne M.; Hall, Steven C.; Witkowska, H. Ewa; Weisgraber, Karl H.

doi:10.1194/jlr.m600545-jlr200

Cited by 55 publications

(81 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lipidation of apoE and its domains has only a small effect on the affinity for apoC-II fibrils, suggesting that there is limited structural change in apoE at the sites of interaction. This is consistent with models of lipoprotein-bound apoE, which suggest that helix three is curved around the lipoprotein surface, with the hydrophobic face interacting with the lipid surface (54,55). This conformation would still allow basic residues on helix three of apoE to interact with alignments of negative charges on amyloid fibrils as shown in Fig.…”

Section: Discussionsupporting

confidence: 74%

Structural Basis for the Recognition and Cross-linking of Amyloid Fibrils by Human Apolipoprotein E

Gunzburg

Perugini

Howlett

2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

Apolipoprotein (apo) E is a well characterized lipid-binding protein in plasma that also exists as a common nonfibrillar component of both cerebral and systemic amyloid deposits. A genetic link between a common isoform of apoE, apoE4, and the incidence of late onset Alzheimer disease has drawn considerable attention to the potential roles of apoE in amyloid-related disease. We examined the interactions of apoE with amyloid fibrils composed of apoC-II and the amyloid-␤ (A␤) peptide. Aggregates of apoE with A␤ and apoC-II are found in Alzheimer and atherosclerotic plaques, respectively. Sedimentation velocity and fibril size distribution analysis showed that apoE3 and E4 isoforms bind and noncovalently cross-link apoC-II fibrils in a similar manner. This ability to cross-link apoC-II fibrils was abolished by the dissociation of the apoE tetramer to monomers or by thrombin cleavage to yield separate N-and C-terminal domains. Preparative ultracentrifuge binding studies indicated that apoE and the isolated N-and C-terminal domains of apoE bind with submicromolar affinities to both apoC-II and A␤ fibrils. Fluorescence quenching and resonance energy transfer experiments confirmed that both domains of apoE interact with apoC-II fibrils and demonstrated that the binding of the isolated N-terminal domain of apoE to apoC-II or A␤ fibrils is accompanied by a significant conformational change with helix three of the domain moving relative to helix one. We propose a model involving the interaction of apoE with patterns of aligned residues that could explain the general ability of apoE to bind to a diverse range of amyloid fibrils.

show abstract

Section: Discussionsupporting

confidence: 74%

Structural Basis for the Recognition and Cross-linking of Amyloid Fibrils by Human Apolipoprotein E

Gunzburg

Perugini

Howlett

2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…From this work, it was shown that the E422k fold was consistent with a helical hairpin (Fig. 1B), providing experimental evidence of the existence of the hairpin structures computationally modeled in this study (54,55). Although our initial modeling efforts have focused on the double-belt model, there is much conjecture on the nature of the lipid-protein interactions.…”

Section: Discussionmentioning

confidence: 99%

Quantifying size distributions of nanolipoprotein particles with single-particle analysis and molecular dynamic simulations

Blanchette

Law

Benner

et al. 2008

Journal of Lipid Research

100

View full text Add to dashboard Cite

Self-assembly of purified apolipoproteins and phospholipids results in the formation of nanometer-sized lipoprotein complexes, referred to as nanolipoprotein particles (NLPs). These bilayer constructs are fully soluble in aqueous environments and hold great promise as a model system to aid in solubilizing membrane proteins. Size variability in the self-assembly process has been recognized for some time, yet limited studies have been conducted to examine this phenomenon. Understanding the source of this heterogeneity may lead to methods to mitigate heterogeneity or to control NLP size, which may be important for tailoring NLPs for specific membrane proteins. Here, we have used atomic force microscopy, ion mobility spectrometry, and transmission electron microscopy to quantify NLP size distributions on the single-particle scale, specifically focusing on assemblies with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and a recombinant apolipoprotein E variant containing the N-terminal 22 kDa fragment (E422k). Four discrete sizes of E422k/DMPC NLPs were identified by all three techniques, with diameters centered at ?14.5, 19, 23.5, and 28 nm. Computer simulations suggest that these sizes are related to the structure and number of E422k lipoproteins surrounding the NLPs and particles with an odd number of lipoproteins are consistent with the double-belt model, in which at least one lipoprotein adopts a hairpin

show abstract

“…Small amounts of CE have previously been reported in fi broblast-and macrophage-derived nHDL ( 45 ). Because cholesteryl esters are much more hydrophobic than cholesterol, it is very likely sequestered in the core of nHDL particle and may constitute the beginnings of a hydrophobic core that yields spheroidal particles ( 71 ). Previous biophysical studies have demonstrated that CE was soluble in phospholipid up to about 3 mol%, whereas above that concentration there was phase separation ( 72 ).…”

Section: Discussion Nhdl Lipidsmentioning

confidence: 99%

Nascent high density lipoproteins formed by ABCA1 resemble lipid rafts and are structurally organized by three apoA-I monomers

Sorci‐Thomas

Owen

Fulp

et al. 2012

Journal of Lipid Research

108

147

View full text Add to dashboard Cite

In humans, the plasma concentration of HDLs has been repeatedly shown to be inversely correlated with the risk of developing coronary heart disease ( 1, 2 ). The concentrations of plasma HDL has been shown to be largely dependent on hepatic ATP-binding cassette transporter A1 (ABCA1) ( 3-5 ), which transports and promotes the effl ux of glycerophosphocholine (PC), free cholesterol (FC), and sphingomyelin (SM) to wild-type apolipoprotein A-I (apoA-I), resulting in the formation of nascent HDLs (nHDLs). Functional mutations in human ABCA1 cause Tangier disease ( 6, 7 ), which is characterized by very low levels of plasma HDL apoA-I. Tangier disease is believed to alter a process termed "reverse cholesterol transport." Although defects in ABCA1 function have been identifi ed by Abstract This report details the lipid composition of nascent HDL (nHDL) particles formed by the action of the ATP binding cassette transporter A1 (ABCA1) on apolipoprotein A-I (apoA-I). nHDL particles of different size (average diameters of ‫ف‬ 12, 10, 7.5, and <6 nm) and composition were purifi ed by size-exclusion chromatography. Electron microscopy suggested that the nHDL were mostly spheroidal. The proportions of the principal nHDL lipids, free cholesterol, glycerophosphocholine, and sphingomyelin were similar to that of lipid rafts, suggesting that the lipid originated from a raft-like region of the cell. Smaller amounts of glucosylceramides, cholesteryl esters, and other glycerophospholipid classes were also present. The largest particles, ‫ف‬ 12 nm and 10 nm diameter, contained ‫ف‬ 43% free cholesterol, 2-3% cholesteryl ester, and three apoA-I molecules. Using chemical cross-linking chemistry combined with mass spectrometry, we found that three molecules of apoA-I in the ‫ف‬ 9-14 nm nHDL adopted a belt-like conformation. The smaller (7.5 nm diameter) spheroidal nHDL particles carried 30% free cholesterol and two molecules of apoA-I in a twisted, antiparallel, double-belt conformation. Overall, these new data offer fresh insights into the biogenesis and structural constraints involved in forming nascent HDL from ABCA1 . -Sorci-Thomas, M. G., J. S. Owen, B. Fulp, S. Bhat, These studies were supported by grants from the National Institutes of Health grants and Abbreviations: BMDM, bone marrow-derived macrophage; CE, cholesteryl ester; DSP, dithiobis(succinimidylpropionate) ; EM, electron microscopy; FC, free cholesterol; FPLC, fast protein liquid chromatography; GP, glycerophospholipids; HEK, human embryonic kidney; HexCer; hexosylceramides; LPC, lyso-glycerophosphocholine; MSCE, mass spectrometer collision energy; NDGGE, nondenaturing gradient gel electrophoresis; nHDL, nascent HDL; PC, glycerophosphocholine; PE, glycerophospho ethanolamine; PG, glycerophosphoglycerol; PI, glyerophos phoinositol; PM, plasma membrane; POPC, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; PS, glycerophosphoserine; rHDL, recombinant HDL; RT, room temperature; SL, sphingolipid; TC, total cholesterol.1 To whom correspondence should be addressed. e-mail...

show abstract

Apolipoprotein E•dipalmitoylphosphatidylcholine particles are ellipsoidal in solution

Cited by 55 publications

References 43 publications

Structural Basis for the Recognition and Cross-linking of Amyloid Fibrils by Human Apolipoprotein E

Structural Basis for the Recognition and Cross-linking of Amyloid Fibrils by Human Apolipoprotein E

Quantifying size distributions of nanolipoprotein particles with single-particle analysis and molecular dynamic simulations

Nascent high density lipoproteins formed by ABCA1 resemble lipid rafts and are structurally organized by three apoA-I monomers

Contact Info

Product

Resources

About