Lipid-bound Structure of an Apolipoprotein E-derived Peptide

Apolipoprotein (apo) E regulates plasma lipid homeostasis through its ability to interact with the low density lipoprotein (LDL) receptor family. Whereas apoE is not a ligand for receptor binding in buffer alone, interaction with lipid confers receptor recognition properties. To investigate the nature of proposed lipid binding-induced conformational changes in apoE, we employed multidimensional heteronuclear NMR spectroscopy to determine the structure of an LDL receptor-active, 58-residue peptide comprising residues 126–183 of apoE in association with the micelle-forming lipid dodecylphosphocholine (DPC). In the presence of 34 mm DPC the peptide forms a continuous amphipathic helix from Glu131 to Arg178. NMR relaxation studies of DPC-bound apoE-(126–183), in contrast to apoE-(126–183) in the presence of TFE, are consistent with an isotropically tumbling peptide in solution giving a global correlation time of ∼12.5 ns. These data indicate that the helical peptide is curved and constrained by a lipid micelle consisting of ∼48 DPC molecules. Although the peptide behaves as if it were tumbling isotropically, spectral density analysis reveals that residues 150–183 have more motional freedom than residues 134–149. These molecular and dynamic features are discussed further to provide insight into the structural basis for the interaction between apoE and the ligand binding repeats of the LDL receptor. Apolipoprotein (apo) E regulates plasma lipid homeostasis through its ability to interact with the low density lipoprotein (LDL) receptor family. Whereas apoE is not a ligand for receptor binding in buffer alone, interaction with lipid confers receptor recognition properties. To investigate the nature of proposed lipid binding-induced conformational changes in apoE, we employed multidimensional heteronuclear NMR spectroscopy to determine the structure of an LDL receptor-active, 58-residue peptide comprising residues 126–183 of apoE in association with the micelle-forming lipid dodecylphosphocholine (DPC). In the presence of 34 mm DPC the peptide forms a continuous amphipathic helix from Glu131 to Arg178. NMR relaxation studies of DPC-bound apoE-(126–183), in contrast to apoE-(126–183) in the presence of TFE, are consistent with an isotropically tumbling peptide in solution giving a global correlation time of ∼12.5 ns. These data indicate that the helical peptide is curved and constrained by a lipid micelle consisting of ∼48 DPC molecules. Although the peptide behaves as if it were tumbling isotropically, spectral density analysis reveals that residues 150–183 have more motional freedom than residues 134–149. These molecular and dynamic features are discussed further to provide insight into the structural basis for the interaction between apoE and the ligand binding repeats of the LDL receptor. The fundamental importance of apolipoprotein (apo) 1The abbreviations used are: apo, apolipoprotein; CSI, chemical shift index; DMPC, dimyristoylphosphatidylcholine; DMPG, dimyristoylphosphatidylglycerol; DPC, dodecylphosphocholine; HSQC, heteronuclear single quantum correlation; LDL, low density lipoprotein; NOE, nuclear Overhauser effect; NOESY, nuclear Overhauser effect enhancement spectroscopy; NT, N-terminal; RMSD, root mean square deviation; TFE, trifluoroethanol; TOCSY, total correlation spectroscopy.1The abbreviations used are: apo, apolipoprotein; CSI, chemical shift index; DMPC, dimyristoylphosphatidylcholine; DMPG, dimyristoylphosphatidylglycerol; DPC, dodecylphosphocholine; HSQC, heteronuclear single quantum correlation; LDL, low density lipoprotein; NOE, nuclear Overhauser effect; NOESY, nuclear Overhauser effect enhancement spectroscopy; NT, N-terminal; RMSD, root mean square deviation; TFE, trifluoroethanol; TOCSY, total correlation spectroscopy. E in plasma lipoprotein metabolism is illustrated by transgenic and gene disruption experiments in mice. Transgenic animals overexpressing apoE manifest decreased plasma cholesterol levels and are protected against diet-induced atherosclerosis (1Shimano H. Yamada N. Katsuki M. Yamamoto K. Gotoda T. Harada K Shimada M. Yazaki T. J. Clin. Invest. 1992; 90: 2084-2091Crossref PubMed Scopus (81) Google Scholar) while apoE-null mice display dramatically elevated plasma lipoprotein and cholesterol levels and are highly susceptible to diet-induced atherosclerosis (2Plump A.S. Smith J.D. Hayek T. Aalto-Setala K. Walsh A. Verstuyft J.G. Rubin E.M. Breslow J.L. Cell. 1992; 71: 343-353Abstract Full Text PDF PubMed Scopus (1866) Google Scholar, 3Zhang S.H. Reddick R.L. Piedrahita J.A. Maeda N. Science. 1992; 258: 468-471Crossref PubMed Scopus (1829) Google Scholar). When complexed to lipoproteins, apoE mediates whole particle uptake and removal from the circulation via members of the LDL receptor family. Biophysical studies reveal that apoE is comprised of two structural domains, a 22-kDa N-terminal (NT) domain and a 10-kDa C-terminal domain (4Wetterau J.R. Aggerbeck L.P. Rall Jr., S.C. Weisgraber K.H. J. Biol. Chem. 1988; 263: 6240-6248Abstract Full Text PDF PubMed Google Scholar, 5Aggerbeck L.P. Wetterau J.R. Weisgraber K.H. Wu C-S.C. Lindgren F.T. J. Biol. Chem. 1988; 263: 6249-6258Abstract Full Text PDF PubMed Google Scholar). The N- and C-terminal domains are connected by a flexible, unstructured, region encompassing amino acids 191–216 that is susceptible to proteolytic cleavage. Studies conducted with isolated domains reveal that the NT domain contains amino acids responsible for binding to the LDL receptor (6Innerarity T.L. Friedlander B.J. Rall Jr., S.C. Weisgraber K.H. Mahley R.W. J. Biol. Chem. 1983; 258: 12341-12347Abstract Full Text PDF PubMed Google Scholar). Several lines of evidence have led to a consensus that localizes the receptor-binding site to residues 136–150 (7Weisgraber K.H. Adv. Protein Chem. 1994; 45: 249-302Crossref PubMed Google Scholar). This region of the protein is rich in basic amino acids, and their proposed role in receptor interactions is consistent with studies demonstrating loss of receptor binding following chemical modification of lysine and arginine residues (8Mahley R.W. Innerarity T.L. Pitas R.E. Weisgraber K.H. Brown J.H. Gross E. J. Biol. Chem. 1977; 252: 7279-7287Abstract Full Text PDF PubMed Google Scholar, 9Weisgraber K.H. Innerarity T.L. Mahley R.W. J. Biol. Chem. 1978; 253: 9053-9062Abstract Full Text PDF PubMed Google Scholar). In the absence of lipid, the isolated NT domain is not recognized by the LDL receptor. On the other hand, complexation with phospholipids results in a particle that binds efficiently to the LDL receptor (6Innerarity T.L. Friedlander B.J. Rall Jr., S.C. Weisgraber K.H. Mahley R.W. J. Biol. Chem. 1983; 258: 12341-12347Abstract Full Text PDF PubMed Google Scholar). These data indicate that a lipid binding-induced conformational adaptation of apoE, which can be mimicked by the isolated NT domain, is an essential feature of apoE function as a ligand for receptor-mediated endocytosis of plasma lipoproteins. X-ray crystallography of lipid-free apoE3-NT has yielded high resolution structures (10Wilson C. Wardell M.R. Weisgraber K.H. Mahley R.W. Agard D.A. Science. 1991; 252: 1817-1822Crossref PubMed Scopus (596) Google Scholar, 11Segelke B.W. Forstner M. Knapp M. Trakhanov S.D. Parkin S. Newhouse Y.M. Bellamy H.D. Weisgraber K.H. Rupp B. Protein Sci. 2000; 9: 886-897Crossref PubMed Scopus (47) Google Scholar). This domain exists as an elongated globular four-helix bundle. Each α-helix segment is amphipathic, orienting its hydrophobic face toward the center of the bundle. The structure of lipid-free apoE3-NT provides a useful starting point for development of models of how the helix bundle alters its structure upon interaction with lipid surfaces to adopt a receptor-active conformation. Weisgraber et al. (12Weisgraber K.H. Lund-Katz S. Phillips M.C. Miller N.E. Tall A.R. High Density Lipoproteins and Atherosclerosis III. Elsevier, Amsterdam1992: 175-181Google Scholar) studied the surface properties of apoE3-NT at the air/water interface on a monolayer balance. These investigators concluded that the protein spreads on the surface to occupy a volume greater than can be accounted for by the globular helix bundle conformation. More recently, NMR spectroscopy studies have provided evidence for a major conformational change in the NT domain upon interaction with lipid (13Lund-Katz S. Zaiou M. Wehrli S. Dhanasekaran P. Baldwin F. Weisgraber K.H. Phillips M.C. J. Biol. Chem. 2000; 275: 34459-34464Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). In 1994, Weisgraber (7Weisgraber K.H. Adv. Protein Chem. 1994; 45: 249-302Crossref PubMed Google Scholar) proposed an “open conformation” in which the segment that helix and helix in the bundle as a which the protein to a continuous hydrophobic et al. E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) the structural of apoE3-NT in by spectroscopy. These investigators a an the of the with its helical to the of DMPC, to adopt a receptor (6Innerarity T.L. Friedlander B.J. Rall Jr., S.C. Weisgraber K.H. Mahley R.W. J. Biol. Chem. 1983; 258: 12341-12347Abstract Full Text PDF PubMed Google Scholar, J. Biol. PubMed Scopus Google Scholar). for has from studies to between in the protein as a function of lipid binding J. Full Text Full Text PDF PubMed Google Scholar, J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). et al. B. J.A. Weisgraber K.H. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar) provided evidence for the conformational by demonstrating that of into is helical in the bundle are by an et al. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar) studied a from 58-residue peptide encompassing the receptor binding region of apoE by of and spectroscopy of the peptide that it is in efficiently into LDL receptor of by with an of the structure of receptor-active apoE peptide by NMR experiments conducted in the presence of the lipid J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In TFE, apoE-(126–183) forms a continuous amphipathic α-helix residues To and investigate the structural of apoE-(126–183) in the presence of lipid, we have the structure of apoE-(126–183) in with the single dodecylphosphocholine (DPC). and features of the apoE-(126–183) DPC-bound structure that apoE binds to the LDL receptor by with more than of its ligand binding The results are discussed in of structural responsible for apoE conformational and binding to the LDL receptor family. of as J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). NMR experiments were on apoE-(126–183) in the presence of 34 mm of and mm as an chemical shift NMR experiments were at on and NMR were F. S. J. A. J. PubMed Scopus Google Scholar) and J. 1994; PubMed Scopus Google Scholar). and spectral of apoE-(126–183) were and experiments to and as by K. NMR of and Google Scholar). of through the of and and heteronuclear relaxation data were at on and the by et al. T. J.D. 1994; PubMed Scopus Google Scholar). The relaxation at time on and The relaxation at time and on the and and on the The for and were the were from the of the from and spectral density as in et al. A. D.A. J. PubMed Scopus Google Scholar). of apoE-(126–183) structures from the and starting with an a M. M. 1988; PubMed Scopus Google Scholar, M. M. Protein 1988; PubMed Scopus Google Scholar) in for X-ray crystallography and Scholar). were from experiments with a of and were to and PubMed Scopus Google Scholar). were on in an A. S. F. 1994; PubMed Scopus Google Scholar) and the M. J. Chem. Scopus Google Scholar). were from the of the in the S. S. M. Protein Sci. 1994; PubMed Scopus Google Scholar). The for the structures are in of structures were from the of structures the Protein 9: PubMed Scopus Google Scholar). the of residues of the structures were and on residues for DPC structures with greater than and greater than for the in structures with greater than and greater than from NOE, structures with greater than and greater than for the in in a and of apoE-(126–183) is in solution and the peptide is not in in the presence of as DPC, as TFE, it a high helical J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). it that mm DPC is to of peptide J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). NMR we the by apoE-(126–183) in to following J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google the of the solution To in a DPC from a solution in and NMR were of DPC the not a change between two not The DPC 34 DPC the of the to by of mm in of a NMR of DPC-bound apoE-(126–183) at the presence of than in J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google were of with with and with and other with and and and In the two N-terminal and the the C-terminal are The structure of apoE-(126–183) NMR spectroscopy upon the NMR chemical shift J. Biol. 1991; PubMed Scopus Google Scholar, 1994; PubMed Scopus Google Scholar) and the of S. S. M. Protein Sci. 1994; PubMed Scopus Google Scholar). of data is illustrated in structure as J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). that DPC-bound apoE-(126–183) is of a single α-helix the from Glu131 to with the and residues evidence of the presence of and for residues and to K. NMR of and Google is of an α-helix is of a The presence of for the a of for shift a of residues from to of a curved amphipathic α-helix J. Chem. 1991; Scopus Google Scholar, N.E. J. Chem. 1992; Scopus Google Scholar). In hydrophobic residues to have a for of from the and of hydrophobic while and In a helical of region of the peptide not and are on the hydrophobic face of the to the interface between the and of the amphipathic and have the and as for be as hydrophobic interactions with other residues in region while the of the is of the hydrophobic face of the is the to the This the for is on the face of the helix and on the of the the for hydrophobic amino as the is to the of the and a with a and a shift These indicate in helix amino acids structural data indicate residues are it with that a of shift is not to the absence of a helical from a curved structure N.E. J. Chem. 1992; Scopus Google Scholar). The structure of apoE-(126–183) from and as of structures of which greater than greater than The structures with the total were for further to J. PubMed Scopus Google of the residues have in the the of the for structures not The from of the is a curved helix residues Glu131 to to a analysis C. 1983; PubMed Scopus Google Scholar). The hydrophobic amino acids for the toward the of the as from the chemical shift for an amphipathic and as for a helix to the surface of a lipid of the structures the of the helix a the peptide is to DPC at not to relaxation analysis that residues are residues to in to of of the structures residues reveals a of and a of be while the helix the of residues with to residues of we to structure the Protein 9: PubMed Scopus Google Scholar). the of residues of the structures were and on residues were with structures as the the more than of the the structures of the in with a DPC micelle of DPC J. Chem. B. 2000; Scopus Google Scholar). the DPC micelle is a and is than we on the correlation the a of how peptide adopt to that the C-terminal of the peptide has a for the micelle than residues 134–149. be discussed has for the interaction of apoE-(126–183) with the receptor. The structures in are the helical with the mean of for for and for for of residues for the helical region of the peptide the the mean for are as for for and for This that the structure is in TFE, the structure display of helix of insight into the of DPC-bound apoE-(126–183), and NMR relaxation as as heteronuclear were The and relaxation as as the heteronuclear at of and are in the residues in apoE-(126–183), the and were not used in the In apoE-(126–183) to an DPC micelle of micelle for DPC is 1994; PubMed Scopus Google Scholar) in an correlation time of of an isotropically tumbling of with the correlation time for DPC apoE-(126–183) to be ∼12.5 ns. reveals the relaxation of apoE-(126–183) to DPC in a globular the and relaxation as as the heteronuclear the for the and is in relaxation as and decreased relaxation as as decreased heteronuclear apoE-(126–183) to DPC residues at the of the peptide as as at the of the peptide This is structural that the peptide forms a α-helix starting from and at with structural residues the and the relaxation in to the at the relaxation to changes in These changes are in the This the correlation the of in not by D.A. A. PubMed Scopus Google Scholar, B. PubMed Scopus Google Scholar). to a of on can the relaxation changes in the relaxation to with the of residues in the the residues Glu131 and to the hydrophobic amphipathic of residues 134–149. and to a hydrophobic of amino acids to the which is decreased to a of and residues and to by a residues and the The time of be by the of the spectral density the spectral density and that the of the from the relaxation and the the spectral density function at is to on time the high spectral density and are to on the time and J.H. PubMed Scopus Google Scholar). the of residues 134–149. These residues a than which a of residues and spectral greater than residues spectral than for residues 134–149. spectral are than that residues elevated which for residues residues and data the for and of between and between and between residues and are between and is a peptide that a lipid binding region and the LDL receptor binding of have that 58-residue peptide major of the NT domain of apoE J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). of the DPC structure of a a helical that Smith Sci. PubMed Scopus Google Scholar). Whereas results with the helical of region of apoE, we a as discussed have residues it not other residues to be for receptor it is that residues are for receptor as illustrated by studies of of Whereas has receptor binding has with further to A. Mahley R.W. J. Biol. Chem. Full Text PDF PubMed Google Scholar). to a role in receptor binding J.A. J. Innerarity T.L. Weisgraber K.H. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). complexed with apoE-(126–183) binds LDL on the surface of J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). apoE-(126–183) contains the residues for receptor it provides a useful for studies to the LDL receptor of we the structure of apoE-(126–183) in association with DPC, a single that a to that of DPC forms is to high resolution NMR 1994; PubMed Scopus Google Scholar). NMR relaxation on DPC have that it a F. T. A. J. Scopus Google Scholar). of in DPC and to DPC forms a curved amphipathic helix from Glu131 to in with the structure of peptide in J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). with the the helix of the DPC-bound peptide by NMR is than that on the basis of spectroscopy the structure of apoE-(126–183) is with to the dynamic of the in In TFE, apoE-(126–183) more in the region between residues and residues and display a of that the further from the the greater the This of dynamic is consistent with a helix tumbling in When to DPC, apoE-(126–183) behaves more isotropically as be for a peptide to the surface of a and have at to relaxation for a globular a more region while residues a more segment of the and are residues with and a of residues and to binding of apoE-(126–183) to the residues and the peptide is a dramatically in to the presence of and and in region receptor interaction by structural adaptation to by ligand binding structure B. C. J. Biol. PubMed Scopus Google Scholar) analysis of apoE-(126–183) results that are in with the NMR two helical and In the helix is a in the for residues This region and the helix from residues to with the and in peptide interaction with lipid surfaces as with structural apoE is to lipoprotein from to properties have for other NMR structures of and in a curved helical between with a that confers a to the structures A. Weisgraber K.H. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). The X-ray structure of an N-terminal of is comprised of a of curved amphipathic J.A. Sci. S. A. PubMed Scopus Google Scholar) the of an These that the features for DPC-bound apoE-(126–183) of of the on structure of DPC-bound apoE-(126–183) has with to apoE ability to to the LDL receptor. and are to display in the presence of lipid, their interaction with of the LDL receptor (13Lund-Katz S. Zaiou M. Wehrli S. Dhanasekaran P. Baldwin F. Weisgraber K.H. Phillips M.C. J. Biol. Chem. 2000; 275: 34459-34464Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). This in to be a of helix in region by the presence of of residues in the presence of lipid interaction with the LDL receptor it is is for binding J.A. J. Innerarity T.L. Weisgraber K.H. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). In the of DPC it is that residues are at the lipid interface while the region between residues and to is that the and of of DPC with the ability of apoE-(126–183) to with the lipid Although residues are not as with the micelle are of helix in region of the be a by lipid interaction of region of the peptide residues of the LDL receptor have discussed in a J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). we features that are to The presence of highly residues ligand binding of the receptor has led to the that recognition be to Although ligand binding to be the Brown J.L. J. Biol. Chem. Full Text PDF PubMed Google experiments a role for other of Brown J.L. J. Biol. Chem. Full Text PDF PubMed Google Scholar, Brown J.L. J. Biol. Chem. 1988; 263: Full Text PDF PubMed Google Scholar). The receptor binding region of apoE a highly surface and interact with the ligand binding in the presence of lipid and surface that interact with a ligand binding residues the surface be for of the peptide at the surface of the with the arginine and lysine residues in ligand binding a has recognized the basic region of apoE interact with of apoE This interaction the apolipoprotein by the lipoprotein in a with to the receptor. When to DPC in J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google apoE-(126–183) an elongated structure in the a single has a of These are consistent with the that apoE with more than at the surface of the receptor in a that be by the structural of ligand binding repeats S.C. PubMed Scopus Google Scholar, N. S.C. PubMed Scopus Google Scholar). structure of the domain of the LDL receptor provides for K. K. Brown J.L. J. Science. PubMed Scopus Google Scholar). is lipoprotein at the LDL receptor its ligand to the structure at it the of the LDL receptor. The feature of structure is that ligand binding repeats and are in through interactions with the of the while other repeats to be by The at following of the lipoprotein the can as an for the two ligand binding and be a These a role for and in ligand binding of the in with and J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). in of lipid structure of apoE-(126–183) helix not at the in the presence and absence of In the structure of apoE3-NT domain, helix at (10Wilson C. Wardell M.R. Weisgraber K.H. Mahley R.W. Agard D.A. Science. 1991; 252: 1817-1822Crossref PubMed Scopus (596) Google Scholar). The amino acids to a at the of C. Protein for a Sci. PubMed Scopus Google Scholar). analysis of the of apoE3-NT provides evidence for the presence of structural analysis the of an between the of and the of to the in a Although a not to and the in the has a high its and not be The for the to a as for a amino conformation. The of a a hydrophobic interaction between and to and is more to used the A. J. M. PubMed Scopus Google Scholar) to hydrophobic in the of and Whereas the of is not to hydrophobic interaction between analysis a hydrophobic interaction between the of and at the of helix the hydrophobic with we that the hydrophobic interaction for of the is provided by a interaction with interactions to between the of helix and residues and 11Segelke B.W. Forstner M. Knapp M. Trakhanov S.D. Parkin S. Newhouse Y.M. Bellamy H.D. Weisgraber K.H. Rupp B. Protein Sci. 2000; 9: 886-897Crossref PubMed Scopus (47) Google Scholar) and residues at the of helix and the of helix forms hydrophobic interactions through its that between and the of helix in to the has a for hydrophobic with the of while a with as by and This to the of at the of helix of the residues as in interactions are apoE The is as is by amino acids are not to between the at and The interaction of with lipid is to by the globular bundle a region between and (7Weisgraber K.H. Adv. Protein Chem. 1994; 45: 249-302Crossref PubMed Google Scholar). that and and and the of bundle B. J.A. Weisgraber K.H. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar) with of helix J. Full Text Full Text PDF PubMed Google Scholar, J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, B. J.A. Weisgraber K.H. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). is the in the of the the the bundle in interactions between residues and the of helix of and hydrophobic interactions between and which to of the has upon disruption of hydrophobic interactions the presence of a for helix structure can the presence of a consensus a C. Protein Scholar). In we that lipid binding-induced of interactions responsible for of helix in lipid-free apoE provides a molecular for the of residues from to LDL receptor recognition properties to the of the region is to be an in apoE NT lipid and that structure residues In to its role in receptor structure in region be an adaptation that to a of the protein with to the lipid This has the for the that the region of apoE a helical structure in the presence of DPC while it is in absence of at the molecular how region can from structure to more to the absence of and it the is for interaction between apoE and the LDL receptor. The lipid surface as a molecular to interactions hydrophobic at of the helix a conformational change from to amphipathic α-helix that and essential of the receptor binding region of from the of for of DPC on the

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