Characterization of Oligomeric Human ATP Binding Cassette Transporter A1

The oligomeric structure of ABCA1 transporter and its function related to the biogenesis of nascent apoA-I-containing particles (LpA-I) were investigated. Using n-dodecylmaltoside and perfluoro-octanoic acid combined with non-denaturing gel, the majority of ABCA1 was found as a tetramer in ABCA1-induced human fibroblasts. Furthermore, using chemical cross-linking and SDS-PAGE, ABCA1 dimers but not the tetramers were found covalently linked. Oligomeric ABCA1 was present in isolated plasma membranes as well as in intracellular compartments. Interestingly, apoA-I was found to be associated with both dimeric and tetrameric, but not monomeric, forms of ABCA1. Neither apoA-I nor lipid molecules did affect ABCA1 oligomerization. Immunoprecipitation analysis showed that oligomeric ABCA1 did not contain other associated proteins. We next investigated the relationship between the oligomeric ABCA1 complex and the structure of LpA-I. Lipid-free apoA-I incubated with normal cells generated LpA-I with diameters between 9.5 and 20 nm. Subsequent isolation of LpA-I followed by cross-linking revealed the presence of four and eight apoA-I molecules per particle, whereas apoA-I incubated with ABCA1 mutant (Q597R) cells was unable to form such particles and remained in the monomeric form. These results demonstrate that: 1) ABCA1 exists as an oligomeric complex; and 2) ABCA1 oligomerization was independent of apoA-I binding and lipid molecules. The findings that the majority of ABCA1 exists as a tetramer that binds apoA-I, together with the observation that LpA-I contains at least four molecules of apoA-I per particle, support the concept that the homotetrameric ABCA1 complex constitutes the minimum functional unit required for the biogenesis of high density lipoprotein particles. The oligomeric structure of ABCA1 transporter and its function related to the biogenesis of nascent apoA-I-containing particles (LpA-I) were investigated. Using n-dodecylmaltoside and perfluoro-octanoic acid combined with non-denaturing gel, the majority of ABCA1 was found as a tetramer in ABCA1-induced human fibroblasts. Furthermore, using chemical cross-linking and SDS-PAGE, ABCA1 dimers but not the tetramers were found covalently linked. Oligomeric ABCA1 was present in isolated plasma membranes as well as in intracellular compartments. Interestingly, apoA-I was found to be associated with both dimeric and tetrameric, but not monomeric, forms of ABCA1. Neither apoA-I nor lipid molecules did affect ABCA1 oligomerization. Immunoprecipitation analysis showed that oligomeric ABCA1 did not contain other associated proteins. We next investigated the relationship between the oligomeric ABCA1 complex and the structure of LpA-I. Lipid-free apoA-I incubated with normal cells generated LpA-I with diameters between 9.5 and 20 nm. Subsequent isolation of LpA-I followed by cross-linking revealed the presence of four and eight apoA-I molecules per particle, whereas apoA-I incubated with ABCA1 mutant (Q597R) cells was unable to form such particles and remained in the monomeric form. These results demonstrate that: 1) ABCA1 exists as an oligomeric complex; and 2) ABCA1 oligomerization was independent of apoA-I binding and lipid molecules. The findings that the majority of ABCA1 exists as a tetramer that binds apoA-I, together with the observation that LpA-I contains at least four molecules of apoA-I per particle, support the concept that the homotetrameric ABCA1 complex constitutes the minimum functional unit required for the biogenesis of high density lipoprotein particles. ABCA1 1The abbreviations used are: ABCA1, ATP binding cassette AI; PAGGE, polyacrylamide non-denaturing gradient gel electrophoresis; apo, apolipoprotein; DSP, dithiobis(succinimidylpropionate); DTT, dithiothreitol; HDL, high density lipoprotein; LpA-I, nascent apoA-I-containing particle; DMEM, Dulbecco's modified Eagle's medium; PBS, phosphate-buffered saline; MWCO, molecular weight cut-off.1The abbreviations used are: ABCA1, ATP binding cassette AI; PAGGE, polyacrylamide non-denaturing gradient gel electrophoresis; apo, apolipoprotein; DSP, dithiobis(succinimidylpropionate); DTT, dithiothreitol; HDL, high density lipoprotein; LpA-I, nascent apoA-I-containing particle; DMEM, Dulbecco's modified Eagle's medium; PBS, phosphate-buffered saline; MWCO, molecular weight cut-off. is a 240-kDa protein belonging to a large family of conserved transmembrane proteins that transport a wide variety of substrates, including lipids, ions, amino acids, peptides, sugars, vitamins, steroid hormones, and drugs across cell membranes (1Croop J.M. Methods Enzymol. 1998; 292: 101-116Crossref PubMed Scopus (53) Google Scholar). ABC transporters have been associated with many diseases such as drug-resistant cancer (2Tusnady G.E. Bakos E. Varadi A. Sarkadi B. FEBS Lett. 1997; 402: 1-3Crossref PubMed Scopus (216) Google Scholar), diabetes (3Thomas P.M. Cote G.J. Wohllk N. Haddad B. Mathew P.M. Rabl W. Aguilar-Bryan L. Gagel R.F. Bryan J. Science. 1995; 268: 426-429Crossref PubMed Scopus (747) Google Scholar), and cystic fibrosis (4Strautnieks S.S. Bull L.N. Knisely A.S. Kocoshis S.A. Dahl N. Arnell H. Sokal E. Dahan K. Childs S. Ling V. Tanner M.S. Kagalwalla A.F. Nemeth A. Pawlowska J. Baker A. Mieli-Vergani G. Freimer N.B. Gardiner R.M. Thompson R.J. Nat. Genet. 1998; 20: 233-238Crossref PubMed Scopus (848) Google Scholar). Apolipoprotein (apo) A-I binding to the extracellular domain of ABCA1 results in the activation of apoA-I lipidation, a key step in the reverse cholesterol transport process, one of the major mechanisms by which high density lipoprotein (HDL) may protect against atherosclerotic vascular disease (5Tall A.R. J. Lipid Res. 1993; 34: 1255-1274Abstract Full Text PDF PubMed Google Scholar, 6Brewer Jr., H.B. Santamarina-Fojo S. Am. J. Cardiol. 2003; 91: 3E-11EAbstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 7Marcil M. Bissonnette R. Vincent J. Krimbou L. Genest J. Circulation. 2003; 107: 1366-1371Crossref PubMed Scopus (35) Google Scholar). The molecular interaction of apoA-I with ABCA1 promotes cholesterol and phospholipid efflux from peripheral cells and macrophages. However, Brewer and colleagues (8Basso F. Freeman L. Knapper C.L. Remaley A. Stonik J. Neufeld E.B. Tansey T. Amar M.J. Fruchart-Najib J. Duverger N. Santamarina-Fojo S. Brewer Jr., H.B. J. Lipid Res. 2003; 44: 296-302Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar) recently reported that hepatic ABCA1 is a key protein for the formation and maintenance of plasma HDL levels. Moreover, the importance of ABCA1 in the lipidation of apoA-I is highlighted by the finding that over 50 mutations in the ABCA1 gene have been associated with a variety of clinically distinct HDL deficiency diseases including Tangier disease and familial HDL deficiency (9Singaraja R.R. Brunham L.R. Visscher H. Kastelein J.J. Hayden M.R. Arterioscler. Thromb. Vasc. Biol. 2003; 23: 1322-1332Crossref PubMed Scopus (224) Google Scholar, 10Brooks-Wilson A. Marcil M. Clee S.M. Zhang L.H. Roomp K. van Dam M. Yu L. Brewer C. Collins J.A. Molhuizen H.O. Loubser O. Ouelette B.F. Fichter K. Ashbourne-Excoffon K.J. Sensen C.W. Scherer S. Mott S. Denis M. Martindale D. Frohlich J. Morgan K. Koop B. Pimstone S. Kastelein J.J.P. Genest Jr., J. Hayden M.R. Nat. Genet. 1999; 22: 336-345Crossref PubMed Scopus (1502) Google Scholar, 11Marcil M. Brooks-Wilson A. Clee S.M. Roomp K. Zhang L.H. Yu L. Collins J.A. van Dam M. Molhuizen H.O. Loubster O. Ouellette B.F. Sensen C.W. Fichter K. Mott S. Denis M. Boucher B. Pimstone S. Genest Jr., J. Kastelein J.J. Hayden M.R. Lancet. 1999; 354: 1341-1346Abstract Full Text Full Text PDF PubMed Scopus (321) Google Scholar). These patients are characterized by excess cholesterol accumulation in macrophages, low plasma HDL levels, and increased risk of coronary artery atherosclerosis (12Oram J.F. Arterioscler. Thromb. Vasc. Biol. 2003; 23: 720-727Crossref PubMed Scopus (210) Google Scholar). ABC transporters typically consist of two multispanning membrane domains that serve as a pathway for the translocation of substrates across membranes and two ATP binding cassettes or nucleotide binding domains that provide the energy for substrate transport (13Sarkadi B. Price E.M. Boucher R.C. Germann U.A. Scarborough G.A. J. Biol. Chem. 1992; 267: 4854-4858Abstract Full Text PDF PubMed Google Scholar, 14Smit L.S. Wilkinson D.J. Mansoura M.K. Collins F.S. Dawson D.C. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 9963-9967Crossref PubMed Scopus (87) Google Scholar). These domains are found either on a single long polypeptide chain, as in the case of cystic fibrosis transmembrane conductance regulator and the multidrug resistance proteins, P-glycoprotein and MRP1, or as a complex of two identical or similar “half-molecule” subunits each having an multispanning membrane domain and an nucleotide binding domain, as found in the TAP1/TAP2 ABC transporters associated with peptide antigen processing. ABCA1 belongs to the first category because it consists of a single polypeptide composed of two arranged halves. Each half contains an multispanning membrane domain followed by a cytoplasmic nucleotide binding domain. A distinguishing feature of ABCA1 is the presence of a large exocytoplasmic domain that connects the first transmembrane segment to the multispanning membrane domain in each half of the protein (15Becq F. Hamon Y. Bajetto A. Gola M. Verrier B. Chimini G. J. Biol. Chem. 1997; 272: 2695-2699Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). Although the ABCA1 molecule is well characterized, very little is known concerning its quaternary structure and its functional properties related to the formation of nascent apoA-I-containing particles. To date, no studies have directly assessed the multimeric structure of human ABCA1. It was therefore the aim of the present study to provide evidence for the existence of oligomeric ABCA1 complex, to demonstrate how ABCA1 forms could be affected by apoA-I or lipid molecules, and to examine the impact of the oligomeric ABCA1 complex on the structure of nascent apoA-I-containing particles in a cell culture model. Patient Selection—For the present study, we selected fibroblasts from three normal control subjects and one patient with Tangier disease (homozygous for Q597R at the ABCA1 gene). The protocol for the study was reviewed and accepted by the Research Ethics Board of the McGill University Health Centre. Separate consent forms for blood sampling, DNA isolation, and skin biopsy were provided. Cell Culture—Human skin fibroblasts were obtained from 3.0-mm of the of patients and control subjects and were in Dulbecco's modified Eagle's with amino acids, and protein cells were by of and University of and were characterized and as J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). and plasma apoA-I was in and against and used was with by to a of of human plasma was a from H. of of Cell by and fibroblasts in were with and acid for 20 were at with n-dodecylmaltoside in the presence of a followed by low to cells were with perfluoro-octanoic acid as by M. C. Y. PubMed Scopus Google Scholar). of cell proteins and at for the were or not with 50 for at and the were by non-denaturing gradient gel as L. Marcil M. J. Genest Jr., J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). and Immunoprecipitation cross-linking was as by and colleagues N. C. A.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) with a were to in and or not with and acid for 20 in were incubated in the presence or of in for at were on for and three with was in and to in of was in each were incubated at for the was and the cells were with were at with 20 and the was to for at in the presence of a complex or ABCA1 was with an as M. B. Marcil M. M. Krimbou L. Genest Jr., J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (87) Google Scholar, B. Denis M. Krimbou L. Marcil M. Genest Jr., J. J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). ABCA1 was by an human The presence of was directly by by using of LpA-I and with was incubated in for at with either normal or Q597R LpA-I particles were isolated by using to LpA-I particles were by using a membrane with a of to of isolated LpA-I was as by and J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar) with of isolated LpA-I generated by normal apoA-I incubated with Q597R or apoA-I incubated cells was to with a protein of an of was in of to a of The was to the for to apoA-I on The was incubated at for with The was by to a of To the that cross-linking affect the of apoA-I molecules per particle, the of to apoA-I was from to and were at and Cell was as B. Denis M. Marcil M. Krimbou L. Genest Jr., J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) with cells were and with as proteins were with for at were with and with The cells were at with 20 n-dodecylmaltoside in the presence of a and with in a at for to cells and of protein from the was to of and incubated on a at The was and three with SDS-PAGE, and of ABCA1 were as and Immunoprecipitation of of ABCA1 was as by and Y. J.F. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). either or normal cells were with for were at with n-dodecylmaltoside in the presence of a followed by low to The were with an were on SDS-PAGE, and ABCA1 was directly by of by particles were by as L. Marcil M. J. Genest Jr., J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). were in the first to by gel and in the to the by polyacrylamide gradient gel high molecular weight protein was as a on each were membranes was directly by by using the present study, we have the multimeric of human ABCA1 transporter in normal fibroblasts with and acid by using both n-dodecylmaltoside and perfluoro-octanoic acid combined with non-denaturing gel These at not the between protein subunits of an of the oligomeric structure of ABCA1 in of ABCA1 by of cell by a n-dodecylmaltoside on non-denaturing gel revealed both a major and The major as an complex, with the molecular of The as a complex, an whereas the with an molecular of is a the other using as a we that the oligomeric forms were to the monomeric form with a molecular of reported for complex ABCA1 protein as by using B. Denis M. Krimbou L. Marcil M. Genest Jr., J. J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). results were with a perfluoro-octanoic acid that the oligomeric ABCA1 was not to the of a Interestingly, we did not ABCA1 with the of a on non-denaturing gel in the of To the oligomeric ABCA1 complex exists in chemical cross-linking was as by and colleagues N. C. A.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). in using ABCA1 at either the monomeric or dimeric molecular and whereas the was in the presence of DTT, of in the other a chemical DSP, was to the of normal fibroblasts to the quaternary structure of ABCA1. We found that ABCA1 in cells with as a as dimers or as a complex with a that for either a or a is a the oligomeric forms to the monomeric ABCA1. To the of oligomeric ABCA1, we to ABCA1 associated with plasma of normal fibroblasts followed by and of ABCA1 on showed three associated with plasma to monomeric, and ABCA1 The three ABCA1 forms were in the intracellular that oligomeric ABCA1 complex was present in normal human fibroblasts with the was ABCA1 in fibroblasts may that are We next the presence of oligomeric ABCA1 complex in cells human ABCA1. We found that the monomeric and dimeric ABCA1 forms were present on whereas ABCA1 was in the presence of the not To that the oligomerization of ABCA1 is not to cell and membrane acid was used as an that formation and the L. M. H. J. J. Lipid Res. 1998; Full Text Full Text PDF PubMed Google Scholar). We found that the or presence of acid did not the of ABCA1. the between apoA-I and ABCA1 have been to be in the lipidation of apoA-I E.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), the was apoA-I could to ABCA1 cells were incubated or not with for at and cross-linking with was in associated with ABCA1 with both dimeric and ABCA1 complex whereas was not found associated with monomeric ABCA1 Moreover, the or presence of apoA-I did not affect ABCA1 oligomerization and To that ABCA1 oligomerization was not on the presence of lipids, cell were or not with and cross-linking was of did not ABCA1 oligomerization not To the oligomeric ABCA1 is a or either or normal fibroblasts were with and ABCA1 was with an in the human no other proteins human ABCA1. Although it be that other proteins with ABCA1 on SDS-PAGE, the low of in cells did not support of ABCA1. or normal cells were with for as were at with in the presence of a followed by low to The were with an were on SDS-PAGE, and ABCA1 was directly by To the relationship between oligomeric ABCA1 complex and the properties of nascent apoA-I-containing particles in cell culture cells either from normal or from Tangier disease (Q597R) subjects in were incubated with in of for at The was by and particles were by in apoA-I-containing particles generated by normal cells with a from 9.5 to 20 apoA-I incubated with ABCA1 mutant (Q597R) cells was unable to form such particles which a molecular and similar to the apoA-I incubated in the cells We next isolated LpA-I particles by using to LpA-I particles were by using a membrane with a of to in the gel, isolated LpA-I particles did not contain of To the structure of LpA-I particles generated by ABCA1, isolated LpA-I particles by oligomeric ABCA1 complex were incubated with cross-linking DSP, a that with the on the of The cross-linking both and but between the of M. M. M. Sci. PubMed Scopus Google Scholar). a apoA-I incubated cells or apoA-I incubated with ABCA1 mutant (Q597R) cells were used as in we that LpA-I particles generated by normal cells either four or eight molecules of apoA-I per and which could be to a by of the with both apoA-I incubated with ABCA1 mutant (Q597R) cells and apoA-I incubated cells remained in the monomeric form To the that cross-linking or of apoA-I affect the of apoA-I molecules per particle, the of to apoA-I was from to and were at and the other apoA-I was used in We found that the of the nor the of apoA-I affected the of apoA-I molecules per not The lipid of ABCA1 transporter been in including the of intracellular lipid and the lipidation of to form nascent M. B. Marcil M. M. Krimbou L. Genest Jr., J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (87) Google Scholar, E.B. Stonik J.A. Jr., Knapper C.L. A. M. N. J. Remaley Santamarina-Fojo S. Brewer Jr., H.B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, L. Denis M. B. M. Marcil M. Genest Jr., J. J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). It is key that we the functional properties of protein and for its the first we present evidence that a majority of human ABCA1 exists in fibroblasts as a with a of oligomerization results were with cells human ABCA1, that the oligomeric ABCA1 complex was not to the of cell Interestingly, the of ABCA1 as assessed by non-denaturing gel 1) that the oligomeric could be an for its in the and to is with studies that other ABC transporters such as cystic fibrosis transmembrane conductance MRP1, or function as either dimers or tetramers M. C. Y. PubMed Scopus Google Scholar, A. R.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Y. Y. S. Zhang J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Although the molecular of apoA-I binding to oligomeric ABCA1 not been the present study that apoA-I binds to both dimeric and ABCA1 complex We that are it is that the ABCA1 complex constitutes the minimum functional structure required for the apoA-I lipidation However, it is that the dimeric ABCA1 is a functional lipid transporter and that other oligomeric ABCA1 function as a regulator for the of a dimeric form. observation that a of oligomeric ABCA1 exists as a in cells did not support such a The of ABCA1 complex as the minimum functional unit required for the lipidation of apoA-I was by results that nascent apoA-I-containing particles generated by the lipid of ABCA1 contain either four or eight molecules of apoA-I per we provide evidence for a functional between oligomeric ABCA1 transporter and the multimeric structure of nascent apoA-I-containing particles. We that functional oligomeric ABCA1 complex is required for the lipid and the of molecules of apoA-I on the results support We demonstrate that apoA-I incubated with ABCA1 mutant (Q597R) cells remained in the monomeric form Furthermore, we have reported that incubated with normal fibroblasts generated with a from to E.B. Stonik J.A. Jr., Knapper C.L. A. M. N. J. Remaley Santamarina-Fojo S. Brewer Jr., H.B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Interestingly, we found that contains four and eight molecules of per particle, whereas incubated with ABCA1 mutant remained in the monomeric form not It is that the minimum functional unit of ABCA1 is a tetramer that four molecules of apoA-I at the whereas the presence of eight molecules of apoA-I per could be by the of two homotetrameric ABCA1 is in with observation that a of ABCA1 exists in cells as an tetramer the oligomeric ABCA1 complex generated multimeric nascent HDL particles of the We have that the presence of LpA-I particles having either four or eight molecules of apoA-I per is an of the presence of LpA-I generated by the oligomeric ABCA1 It is that the of LpA-I particles was in to the cross-linking cross-linking may have between LpA-I to of apoA-I that were not by Although be with of to apoA-I and a cross-linking at or at did not in of the of apoA-I molecules per Although ABCA1 Q597R and were found to not and to the plasma showed the of binding to apoA-I B. Denis M. Krimbou L. Marcil M. Genest Jr., J. J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, B. Denis M. Marcil M. Krimbou L. Genest Jr., J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). These results that the apoA-I lipidation in either Q597R or ABCA1 is not by oligomerization of ABCA1. Furthermore, a mutant of ABCA1 in which the large extracellular is with A. Marcil M. Clee S.M. Zhang L.H. Roomp K. van Dam M. Yu L. Brewer C. Collins J.A. Molhuizen H.O. Loubser O. Ouelette B.F. Fichter K. Ashbourne-Excoffon K.J. Sensen C.W. Scherer S. Mott S. Denis M. Martindale D. Frohlich J. Morgan K. Koop B. Pimstone S. Kastelein J.J.P. Genest Jr., J. Hayden M.R. Nat. Genet. 1999; 22: 336-345Crossref PubMed Scopus (1502) Google Scholar), was found to that is not for ABCA1 We are the for the ABCA1 transporter to form an oligomeric It is well that of a of which studies from and have that ABCA1 by the protein pathway an in the apoA-I lipidation B. Denis M. Krimbou L. Marcil M. Genest Jr., J. J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, B. Denis M. Marcil M. Krimbou L. Genest Jr., J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, B. N. W. A.R. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, R.R. S. A. J. R. J.M. V. Zhang L.H. M. Chimini G. C.L. Hayden M.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). It is that apoA-I ABCA1 ABCA1 oligomerization. Although apoA-I binds to both the dimeric and the ABCA1, the presence or of apoA-I molecules did not affect the oligomerization of ABCA1 in cell culture and are required to a of apoA-I in the ABCA1 oligomerization The molecular of apoA-I molecules nascent LpA-I particles by the lipid of the oligomeric ABCA1 complex not been However, because of the of cholesterol in the extracellular to cholesterol to it is that nascent LpA-I particles are We have that the of LpA-I particles may be to high in M. B. Marcil M. M. Krimbou L. Genest Jr., J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (87) Google Scholar, S. J. Biol. Chem. Full Text PDF PubMed Google Scholar). However, it is that the high of apoA-I molecules per as in the present study may to the of LpA-I particles and Although the of apoA-I molecules nascent particles is M.K. M. H. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar) a to as the for LpA-I particles two molecules of two molecules of apoA-I are on of each a that the of the phospholipid in an in the for between the two molecules. It is that the of two apoA-I molecules on not be the as that found on nascent LpA-I four or eight molecules of the presence of of nascent having both a and of apoA-I molecules the that apoA-I on particles are O. D. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). However, we to that no was to to a concerning the of apoA-I molecules nascent in is a of apoA-I lipidation by the oligomeric ABCA1 The of apoA-I nascent particles which are The results in study provide a for a apoA-I lipidation pathway that oligomeric ABCA1 complex in peripheral in a key functional in the biogenesis of nascent HDL particles. We H. for

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