Apolipoprotein B-containing Lipoprotein Particle Assembly

We previously proposed that the N-terminal 1000-residue βα1 domain of apolipoprotein B (apoB) forms a bulk lipid pocket homologous to that of lamprey lipovitellin. In support of this “lipid pocket” hypothesis, we demonstrated that apoB:1000 (residues 1-1000) is secreted by a stable transformant of McA-RH7777 cells as a monodisperse particle with high density lipoprotein 3 (HDL3) density. In contrast, apoB:931 (residues 1-931), missing only 69 residues of the sequence homologous to lipovitellin, was secreted as a particle considerably more dense than HDL3. In the present study we have determined the stoichiometry of the lipid component of the apoB:931 and apoB:1000 particles. The secreted 3Hglycerol-labeled apoB:1000 particles, isolated by nondenaturing gradient gel electrophoresis, contained 50 phospholipid (PL) and 11 triacylglycerol (TAG) molecules/particle. In contrast, apoB:931 particles contained only a few molecules of PL and were devoid of TAG. The unlabeled apoB:1000 particles, isolated by immunoaffinity chromatography, contained 56 PL, 8 TAG, and 7 cholesteryl ester molecules/particle. The surface to core lipid ratio of apoB:1000-containing particles was ∼4:1 and was not affected by oleate supplementation. Although very small amounts of microsomal triglyceride transfer protein (MTP) were associated with apoB:1000 particles, it never approached a 1:1 molar ratio of MTP to apoB. These results support a model in which (i) the first 1000 amino acid residues of apoB are competent to complete the lipid pocket without a structural requirement for MTP; (ii) a portion, or perhaps all, of the amino acid residues between 931 and 1000 of apoB-100 are critical for the formation of a stable, bulk lipid-containing nascent lipoprotein particle, and (iii) the lipid pocket created by the first 1000 residues of apoB-100 is PL-rich, suggesting a small bilayer type organization and has a maximum capacity on the order of 50 molecules of phospholipid. We previously proposed that the N-terminal 1000-residue βα1 domain of apolipoprotein B (apoB) forms a bulk lipid pocket homologous to that of lamprey lipovitellin. In support of this “lipid pocket” hypothesis, we demonstrated that apoB:1000 (residues 1-1000) is secreted by a stable transformant of McA-RH7777 cells as a monodisperse particle with high density lipoprotein 3 (HDL3) density. In contrast, apoB:931 (residues 1-931), missing only 69 residues of the sequence homologous to lipovitellin, was secreted as a particle considerably more dense than HDL3. In the present study we have determined the stoichiometry of the lipid component of the apoB:931 and apoB:1000 particles. The secreted 3Hglycerol-labeled apoB:1000 particles, isolated by nondenaturing gradient gel electrophoresis, contained 50 phospholipid (PL) and 11 triacylglycerol (TAG) molecules/particle. In contrast, apoB:931 particles contained only a few molecules of PL and were devoid of TAG. The unlabeled apoB:1000 particles, isolated by immunoaffinity chromatography, contained 56 PL, 8 TAG, and 7 cholesteryl ester molecules/particle. The surface to core lipid ratio of apoB:1000-containing particles was ∼4:1 and was not affected by oleate supplementation. Although very small amounts of microsomal triglyceride transfer protein (MTP) were associated with apoB:1000 particles, it never approached a 1:1 molar ratio of MTP to apoB. These results support a model in which (i) the first 1000 amino acid residues of apoB are competent to complete the lipid pocket without a structural requirement for MTP; (ii) a portion, or perhaps all, of the amino acid residues between 931 and 1000 of apoB-100 are critical for the formation of a stable, bulk lipid-containing nascent lipoprotein particle, and (iii) the lipid pocket created by the first 1000 residues of apoB-100 is PL-rich, suggesting a small bilayer type organization and has a maximum capacity on the order of 50 molecules of phospholipid. Apolipoprotein (apo) 1The abbreviations used are: apo, apolipoprotein; BSA, bovine serum albumin; CE, cholesteryl ester; DAG, diacylglycerol; DMEM, Dulbecco's modified Eagle's medium; ER, endoplasmic reticulum; FBS, fetal bovine serum; HDL, high density lipoprotein; LDL, low density lipoprotein; LV, lipovitellin; MTP, microsomal triglyceride transfer protein; NDGGE, nondenaturing gradient gel electrophoresis; PL, phospholipids; PBS, phosphate-buffered saline; TAG, triacylglycerol; VLDL, very low density lipoprotein; PVDF, polyvinylidene difluoride. 1The abbreviations used are: apo, apolipoprotein; BSA, bovine serum albumin; CE, cholesteryl ester; DAG, diacylglycerol; DMEM, Dulbecco's modified Eagle's medium; ER, endoplasmic reticulum; FBS, fetal bovine serum; HDL, high density lipoprotein; LDL, low density lipoprotein; LV, lipovitellin; MTP, microsomal triglyceride transfer protein; NDGGE, nondenaturing gradient gel electrophoresis; PL, phospholipids; PBS, phosphate-buffered saline; TAG, triacylglycerol; VLDL, very low density lipoprotein; PVDF, polyvinylidene difluoride. B has a fundamental role in the transport and metabolism of plasma triacylglycerols (TAG) and cholesterol and is synthesized primarily in hepatocytes and enterocytes (1Schumaker V.N. Phillips M.L. Chatterton J.E. Adv. Protein Chem. 1994; 45: 205-248Crossref PubMed Scopus (118) Google Scholar, 2Fisher E.A. Ginsberg H.N. J. Biol. Chem. 2002; 277: 17377-17380Abstract Full Full PubMed Scopus Google Scholar, J. J. Full Full PubMed Scopus Google is present as a lipoprotein particle and in forms in apoB-100 and protein of amino acid residues E.A. Ginsberg H.N. J. Biol. Chem. 2002; 277: 17377-17380Abstract Full Full PubMed Scopus Google is structural component for the formation and of very low density the of low density and is primarily in N-terminal of is by a of the apoB that a to a E.A. Ginsberg H.N. J. Biol. Chem. 2002; 277: 17377-17380Abstract Full Full PubMed Scopus Google is for the formation and of and is in and in the of E.A. Ginsberg H.N. J. Biol. Chem. 2002; 277: 17377-17380Abstract Full Full PubMed Scopus Google The B are in and with the lipoprotein particle metabolism 45: PubMed Scopus Google of the and of this it has to the structural for of this protein J. PubMed Scopus Google Scholar, PubMed Scopus Google The of the is synthesized on the of the endoplasmic the N-terminal is the and is as a small lipoprotein of of the N-terminal domain of apoB is for lipoprotein J. Full PubMed Google Scholar, J. Biol. Chem. Full Full PubMed Scopus Google Scholar, J. Biol. Chem. Full Full PubMed Scopus Google In the first in apoB the formation of a small particle in the high density lipoprotein density has that the of the N-terminal of apoB-100 is for the of particles J. Biol. Chem. Full Full PubMed Scopus Google Scholar, J. Biol. Chem. Full Full PubMed Scopus Google Scholar, J. Biol. Chem. Full PubMed Google Scholar, J. Biol. Chem. Full Full PubMed Scopus Google Scholar, J. Biol. Chem. Full Full PubMed Scopus Google and that microsomal triglyceride transfer protein (MTP) has a critical role in the and of J. J. Full Full PubMed Scopus Google Scholar, J. PubMed Scopus Google the domain in the N-terminal of apoB that is for the of particle the structural of the competent the lipid of this nascent particle, the by which MTP lipid to the nascent and the in the this transfer are not and The the only protein component of the LDL, has a the and the 1994; PubMed Scopus Google Scholar, J. J. Full Full PubMed Google the of the and are the type in PubMed Scopus Google Scholar, J. Full PubMed Google Scholar, Adv. Protein Chem. 1994; 45: PubMed Google we have proposed that of apoB-100 with lipid J. Full Full PubMed Google The in and we have proposed that the of apoB-100 PubMed Scopus Google Scholar, J. Full PubMed Google Scholar, Adv. Protein Chem. 1994; 45: PubMed Google The βα1 domain of the first 1000 amino acid residues of the is a of and J. J. Full Full PubMed Google has proposed to in 1994; PubMed Scopus Google Scholar, J. Full Full PubMed Google and has sequence and to lamprey J. Full Full PubMed Google Scholar, J. Biol. Chem. Full PubMed Google Scholar, PubMed Scopus Google Scholar, J. J. J. J. Biol. PubMed Scopus Google on sequence between the N-terminal domain of apoB and LV, we proposed J. Full Full PubMed Google Scholar, J. Full Full PubMed Google that formation of a lipid pocket is for lipid transfer to lipoprotein particles. We J. Full Full PubMed Google Scholar, J. 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The particles in are in and are in of the in and it is this that the of the particles with of In a few the particles have a of of the in suggesting that the particles to have a of the model for in study J. Google is for the as the in are is that is and to the of the MTP with in a 1:1 2002; PubMed Scopus Google that and were with or apoB-100 nondenaturing by and with and MTP and apoB:1000 were of the by and with apoB-100 and the of MTP, small in in the secreted apoB:1000-containing particles 2002; PubMed Scopus Google on results we that MTP structural component of the lipid that of MTP to of this between MTP and cells were in for and was to The gel was with and the to apoB:1000 was and by In the was to NDGGE, and were and with The to by of a was by amino acid We were in MTP in apoB:1000-containing particles by or amino acid not These results that MTP is not a structural component of the lipid pocket not role in the of the apoB:1000-containing particles. In J. Full Full PubMed Google Scholar, J. Full Full PubMed Google on sequence between the βα1 domain of the first 1000 amino acid residues of the and LV, we proposed that formation of lipid pocket is for lipid transfer to lipoprotein particles. We that of particle the βα1 domain a or the lipid pocket is by of the of the βα1 domain homologous to the and of with MTP J. Full Full PubMed Google Scholar, J. 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PubMed Scopus Google is the by which apoB is a for the of lipid particles apoB is the model (1Schumaker V.N. Phillips M.L. Chatterton J.E. Adv. Protein Chem. 1994; 45: 205-248Crossref PubMed Scopus (118) Google In this the N-terminal of apoB is in the of the it the of apoB this is the bilayer to the nascent of this model is that by for in the microsomal has (1Schumaker V.N. Phillips M.L. Chatterton J.E. Adv. Protein Chem. 1994; 45: 205-248Crossref PubMed Scopus (118) Google it that the or of model for the of apoB has by and PubMed Scopus Google These have that the formation of the lipoprotein particle by a the of PL by the N-terminal by of core by the of and PubMed Scopus Google results that apoB:1000-containing particles are and a few molecules are with the model proposed by and PubMed Scopus Google results that apoB:931 not the structural to lipoprotein and only a few molecules of PL, apoB:1000 forms a particle with a surface to core lipid ratio of are to by J. Biol. Chem. 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