The structure of vitellogenin provides a molecular model for the assembly and secretion of atherogenic lipoproteins 1 1Edited by A. R. Fersht

Mann, Christopher; Anderson, Timothy A.; Read, Jacqueline; Chester, Sean; Harrison, Georgina B.; Köchl, Silvano; Ritchie, Penelope J.; Bradbury, Paul; Hussain, Faheem; Amey, Joanna S.; Vanloo, Berlinda; Rosseneu, Maryvonne; Infante, R; Hancock, John M.; Levitt, David G.; Banaszak, Leonard J.; Scott, James; Shoulders, Carol C.

doi:10.1006/jmbi.1998.2298

Cited by 180 publications

(212 citation statements)

References 65 publications

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“…The very N-terminal ∼6% of apoB is proposed to fold into a β-barrel that we demonstrate lacks phospholipid remodeling capability. Yet this domain binds MTP and may serve as an important docking site for MTP during the early stages of lipoprotein assembly (9). Phospholipid binding could begin as early as during the translation of the first half of the proposed α-helical domain, B6.4−10.…”

Section: Discussionmentioning

confidence: 99%

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Defining Lipid-Interacting Domains in the N-Terminal Region of Apolipoprotein B

et al. 2006

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Apolipoprotein B (ApoB) is a nonexchangeable apolipoprotein that dictates the synthesis of chylomicrons and very low density lipoproteins. ApoB is the major protein in low density lipoprotein, also known as the "bad cholesterol" that is directly implicated in atherosclerosis. It has been suggested that the N-terminal domain of apoB plays a critical role in the formation of apoB-containing lipoproteins through the initial recruitment of phospholipids in the endoplasmic reticulum. However, very little is known about the mechanism of lipoprotein nucleation by apoB. Here we demonstrate that a strong phospholipid remodeling function is associated with the predicted α-helical and C-sheet domains in the N-terminal 17% of apoB (B17). Using dimyristoylphosphatidylcholine (DMPC) as a model lipid, these domains can convert multilamellar DMPC vesicles into discoidal-shaped particles. The nascent particles reconstituted from different apoB domains are distinctive and compositionally homogenous. This phospholipid remodeling activity is also observed with egg phosphatidylcholine (egg PC) and is therefore not DMPC dependent. Using kinetic analysis of the DMPC clearance assay, we show that the identified phospholipid binding sequences all map to the surface of the lipid binding pocket in the B17 model based on the homologous protein, lipovitellin. Since both B17 and microsomal triglyceride transfer protein (MTP), a critical chaperone during lipoprotein assembly, are homologous to lipovitellin, the identification of these phospholipid remodeling sequences in B17 provides important insights into the potential mechanism that initiates the assembly of apoB-containing lipoproteins.Apolipoprotein B (apoB) is the only known nonexchangeable apolipoprotein in humans. It is the major protein component of low density lipoprotein (LDL), a major risk factor for atherosclerosis. Two forms of apoB are synthesized in humans, B48 from in small intestine and B100 in the liver (1). The production of B48 is the result of a tissue specific mRNA processing occurring in the small intestine (2,3). The translation of B48 and B100 in the endoplasmic reticulum (ER) is directly coupled with the assembly of two major classes of lipoproteins: chylomicrons and very low density lipoproteins (VLDL) (4).Although an apoB structure at atomic resolution is still unavailable, it is generally accepted that the full length apoB has an βα1-β1-α2-β2-α3 pentapartite domain organization, in which α represents predominantly α-helical structures and β corresponds to β-sheets (5). According to this model, apoB is depicted as a belt wrapped around a lipoprotein particle (6). Evidence from electron microscopy indicates that the N-terminus of apoB, largely the βα1 domain, is globularly folded and protrudes away from the LDL particle (7,8). These findings are consistent

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Section: Discussionmentioning

confidence: 99%

“…with the observation that the N-terminal ∼20% of apoB is homologous to a globular protein, lipovitellin (9,10). Lipovitellin is a nutrient storage protein in the egg yolk derived from vitellogenesis (11).…”

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confidence: 97%

Defining Lipid-Interacting Domains in the N-Terminal Region of Apolipoprotein B

et al. 2006

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“…The N-terminal ␤␣1 superdomain, corresponding to the first 20.5% of apoB, has both ␣-helical and ␤-sheet secondary structure and has a putative globular tertiary fold (8,9). The ␤␣1 domain is required for the initial assembly of TRL in enterocytes and hepatocytes (4).…”

mentioning

confidence: 99%

“…␤␣1 is moderately homologous to the lipid storage protein lipovitellin (LV) (Fig. 2) (8,9). The high resolution crystal structure of LV has been used to construct structural models of ␤␣1 (8,10).…”

mentioning

confidence: 99%

“…1B, predicts that the ␤␣1 superdomain contains four domains as follows: an N-terminal ␤-barrel (apoB5.9); an ␣-helical domain (␣HD, apoB6 -13); and two A␤S-rich domains called the C-sheet (apoB13-17) and A-sheet (apoB17-20.5). At the center of the dimeric LV structure is a small lipid droplet stabilized by the N-terminal half of the ␣HD, the C-sheet, and A-sheet domains of both monomers (8,9). The structure of the isolated domains of apoB are consistent with the LV model, based on circular dichroism spectroscopy, crosslinking, and limited proteolysis (11).…”

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confidence: 99%

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Surface Tensiometry of Apolipoprotein B Domains at Lipid Interfaces Suggests a New Model for the Initial Steps in Triglyceride-rich Lipoprotein Assembly

Mitsche¹,

Packer²,

Brown³

et al. 2014

Journal of Biological Chemistry

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Background: Apolipoprotein B (apoB) is the essential protein component of chylomicrons and very low density lipoprotein that transports lipids in plasma. Results: Domains of apoB interact with model membranes dependent on lipid composition and surface pressure. Conclusion: ApoB domains interact with membranes to initiate lipid recruitment. Significance: The apoB lipid recruitment mechanism provides a target to regulate the secretion of VLDL.

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Microsomal Triglyceride Transfer Protein

Wetterau¹

2002

Wiley Encyclopedia of Molecular Medicine

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Microsomal triglyceride transfer protein (MTP)is critical for the assembly and secretion of apolipoprotein B (apoB) lipoproteins. Its activity is classically measured by incubating purified MTP or cellular homogenates with donor vesicles containing radiolabeled lipids, precipitating the donor vesicles, and measuring the radioactivity transferred to acceptor vesicles. Here, we describe a simple, rapid, and sensitive fluorescence assay for MTP. In this assay, purified MTP or cellular homogenates are incubated with small unilamellar donor vesicles containing quenched fluorescent lipids (triacylglycerols, cholesteryl esters, and phospholipids) and different types of acceptor vesicles made up of phosphatidylcholine or phosphatidylcholine and triacylglycerols. Increases in fluorescence attributable to MTP-mediated lipid transfer are measured after 30 min. MTP's lipid transfer activity could be assayed using apoB lipoproteins but not with high density lipoproteins as acceptors. The assay was used to measure MTP activity in cell and tissue homogenates. Furthermore, the assay was useful in studying the inhibition of the cellular as well as purified MTP by its antagonists.This new method is amenable to automation and can be easily adopted for large-scale, high-throughput screening. -Athar, H., J. Iqbal, X-C. Jiang, and M. M. Hussain. A simple, rapid, and sensitive fluorescence assay for microsomal triglyceride transfer protein. J. Lipid Res. 2004. 45: 764-772. Supplementary key words lipoprotein assembly • cholesteryl esters • phospholipids • triacylglycerol • apolipoprotein B Abbreviations: apoB, apolipoprotein B; CE, cholesteryl ester; PC, phosphatidylcholine; PL, phospholipid; MTP, microsomal triglyceride transfer protein; TAG, triacylglycerol.

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The structure of vitellogenin provides a molecular model for the assembly and secretion of atherogenic lipoproteins 1 1Edited by A. R. Fersht

Cited by 180 publications

References 65 publications

Defining Lipid-Interacting Domains in the N-Terminal Region of Apolipoprotein B

Defining Lipid-Interacting Domains in the N-Terminal Region of Apolipoprotein B

Surface Tensiometry of Apolipoprotein B Domains at Lipid Interfaces Suggests a New Model for the Initial Steps in Triglyceride-rich Lipoprotein Assembly

Microsomal Triglyceride Transfer Protein

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