Abstract
This review highlights recent advances in structural studies on low density lipoprotein (LDL) with particular emphasis on the apolipoprotein moiety of LDL, apolipoprotein B100 (apoB100). Various molecular aspects of LDL are outlined and obstacles to structure determination are addressed. In this context, the prevailing conceptions of the molecular assembly of LDL and how the synergy of complementary biochemical, biophysical and molecular simulation approaches has lead to the current structural model of LDL are discussed. Evidence is presented that structural heterogeneity and the intrinsic dynamics of LDL are key determinants of the functionality of LDL in both health and disease. Some key research directions, remaining open questions and rapidly emerging new concepts for medical applications of LDL, are furthermore outlined. The article concludes by providing an outlook concerning promising future strategies for the clarification of the molecular details of LDL, in particular of apoB100, combining recent advances in molecular modeling with developments of novel experimental techniques. Although new insights into the molecular organization of LDL are forthcoming, many open questions remain unanswered. The major challenge of the next decade will certainly be the elucidation of the molecular structural and dynamic features of apoB100.
Similar content being viewed by others
Abbreviations
- LDL:
-
Low density lipoprotein
- apoB100:
-
Apolipoprotein B100
- SAXS:
-
Small angle X-ray scattering
- SANS:
-
Small angle neutron scattering
- MRI:
-
Magnetic resonance imaging
- VLDL:
-
Very low density lipoprotein
- IDL:
-
Intermediate density lipoprotein
References
Anderson TA, Levitt DG, Banaszak LJ (1998) The structural basis of lipid interactions in lipovitellin, a soluble lipoprotein. Structure 6:895–909. doi:10.1016/S0969-2126(98)00091-4
Atkinson D, Small DM (1986) Recombinant lipoproteins: implication for structure and assembly of native lipoproteins. Annu Rev Biophys Biophys Chem 15:403. doi:10.1146/annurev.bb.15.060186.002155
Atkinson D, Deckelbaum RJ, Small DM, Shipley GG (1977) Structure of human plasma low-density lipoproteins: molecular organization of the central core. Proc Natl Acad Sci USA 74:1042–1046. doi:10.1073/pnas.74.3.1042
Austin MA, Edwards KL (1996) Small, dense low density lipoproteins, the insulin resistance syndrome and noninsulin-dependent diabetes. Curr Opin Lipidol 7:167–171
Austin MA, King MC, Vranizan KM, Krauss RM (1990) Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. Circulation 82:495–506
Aviram M, Lund-Katz S, Phillips MC, Chait A (1988) The influence of the triglyceride content of low density lipoprotein on the interaction of apolipoprotein B-100 with cells. J Biol Chem 263:16842–16848
Aviram M, Dankner G, Cogan U, Hochgraf E, Brook JG (1992) Lovastatin inhibits low-density lipoprotein oxidation and alters its fluidity and uptake by macrophages: in vitro and in vivo studies. Metabolism 41:229–235. doi:10.1016/0026-0495(92)90263-A
Banuelos S, Arrondo JLR, Goni FM, Pifat G (1995) Surface-core relationships in human low density lipoprotein as studied by infrared spectroscopy. J Biol Chem 270:9192–9196
Baumstark MW, Kreutz W, Berg A, Frey I, Keul J (1990) Structure of human low-density lipoprotein subfractions, determined by X-ray small-angle scattering. Biochim Biophys Acta 1037:48–57
Beisiegel U, St Clair RW (1996) An emerging understanding of the interactions of plasma lipoproteins with the arterial wall that leads to the development of atherosclerosis. Curr Opin Lipidol 7:265–268
Binder CJ, Chang MK, Shaw PX, Miller YI, Hartvigsen K, Dewan A et al (2002) Innate and acquired immunity in atherogenesis. Nat Med 8:1218–1226. doi:10.1038/nm1102-1218
Boren J, Lee I, Zhu W, Arnold K, Taylor S, Innerarity TL (1998) Identification of the low density lipoprotein receptor-binding site in apolipoprotein B100 and the modulation of its binding activity by the carboxyl terminus in familial defective apo-B100. J Clin Invest 101:1084–1093. doi:10.1172/JCI1847
Brown MS, Goldstein JL (1976) Receptor-mediated control of cholesterol metabolism. Science 191:150–154. doi:10.1126/science.174194
Burch WL, Herscovitz H (2000) Disulfide bonds are required for folding and secretion of apolipoprotein B regardless of its lipidation state. J Biol Chem 275:16267–16274. doi:10.1074/jbc.M000446200
Camejo G, Hurtcamejo E, Wiklund O, Bondjers G (1998) Association of apo B lipoproteins with arterial proteoglycans: pathological significance and molecular basis. Atherosclerosis 139:205–222. doi:10.1016/S0021-9150(98)00107-5
Cardin AD, Chao J, Donaldson VH, Jackson RL, Margolius HS, Witt KR (1984) Degradation of apolipoprotein-B-100 of human-plasma low-density lipoproteins by tissue and plasma kallikreins. J Biol Chem 259:8522–8528
Caslake MJ, Stewart G, Day SP, Daly E, McTaggart F, Chapman MJ et al (2003) Phenotype-dependent and -independent actions of rosuvastatin on atherogenic lipoprotein subfractions in hyperlipidaemia. Atherosclerosis 171:245–253. doi:10.1016/j.atherosclerosis.2003.08.025
Chapman MJ, Laplaud PM, Luc G, Forgez P, Bruckert E, Goulinet S et al (1988) Further resolution of the low density lipoprotein spectrum in normal human plasma: physicochemical characteristics of discrete subspecies separated by density gradient ultracentrifugation. J Lipid Res 29:442–458
Chapman MJ, Guerin M, Bruckert E (1998) Atherogenic, dense low-density lipoproteins. Pathophysiology and new therapeutic approaches. Eur Heart J 19(Suppl A):A24–A30
Chatterton JE, Phillips ML, Curtiss LK, Milne RW, Marcel YL, Schumaker VN (1991) Mapping apolipoprotein B on the low density lipoprotein surface by immunoelectron microscopy. J Biol Chem 266:5955–5962
Chatterton JE, Phillips ML, Curtiss LK, Milne R, Fruchart JC, Schumaker VN (1995a) Immunoelectron microscopy of low density lipoproteins yields a ribbon and bow model for the conformation of apolipoprotein b on the lipoprotein surface. J Lipid Res 36:2027–2037
Chatterton JE, Schlapfer P, Bütler E, Gutierrez MM, Puppione DL, Pullinger CR et al (1995b) Identification of apolipoprotein B 100 Polymorphisms that affect low-density lipoprotein metabolism: description of a new approach involving monoclonal antibodies and dynamic light scattering. Biochemistry 34:9571–9580. doi:10.1021/bi00029a034
Chen S-H, Yang C-Y, Chen PF, Setzer D, Tanimura M, Li W-H et al (1986) The complete cDNA and amino acid sequence of human apolipoprotein B-100. J Biol Chem 261:2918–2921
Chen GC, Zhu S, Hardman DA, Schilling JW, Lau K, Kane JP (1989) Structural domains of human apolipoprotein B-100. J Biol Chem 264:14369–14375
Chen GC, Liu W, Duchateau P, Allaart J, Hamilton RL, Mendel CM et al (1994) Conformational differences in human apolipoprotein B-100 among subspecies of low density lipoproteins (LDL). J Biol Chem 269:29121–29128
Cojoc D, Ferrari E, Garbin V, Di Fabrizio E, Amenitsch H, Rappolt M, Sartori B, Laggner P, Burghammer M, Riekel C (2007) Scanning x-ray microdiffraction of optically manipulated liposomes. Appl Phys Lett 91:234107-1–234107-3
Corbin IR, Li H, Chen J, Lund-Katz S, Zhou R, Glickson JD et al (2006) Low-density lipoprotein nanoparticles as magnetic resonance imaging contrast agents. Neoplasia 8:488–498. doi:10.1593/neo.05835
Coronado-Gray A, Van Antwerpen R (2003) The physical state of the LDL core influences the conformation of apolipoprotein B-100 on the lipoprotein surface. FEBS Lett 533:21–24. doi:10.1016/S0014-5793(02)03731-6
Dachet C, Motta C, Neufcour D, Jacotot B (1990) Fluidity changes and chemical composition of lipoproteins in type IIa hyperlipoproteinemia. Biochim Biophys Acta 1046:64–72
Dashti N, Gandhi M, Liu X, Lin X, Segrest JP (2002) The N-terminal 1000 residues of apolipoprotein B associate with microsomal triglyceride transfer protein to create a lipid transfer pocket required for lipoprotein assembly. Biochemistry 41:6978–6987. doi:10.1021/bi011757l
Deckelbaum RJ, Shipley GG, Small DM, Lees RS, George PK (1975) Thermal transitions in human plasma low density lipoproteins. Science 190:392–394. doi:10.1126/science.170681
Deckelbaum RJ, Shipley GG, Small DM (1977) Structure and interactions of lipids in human plasma low density lipoproteins. J Biol Chem 252:744–754
Dejager S, Bruckert E, Chapman MJ (1993) Dense low lipoprotein subspecies with diminished oxidative resistance predominate in combined hyperlipidemia. J Lipid Res 34:295–308
Finer EG, Henry R, Leslie RB, Robertson RN (1975) NMR studies of pig low-and high-density serum lipoproteins. Molecular motions and morphology. Biochim Biophys Acta 380:320–337
Firestone RA (1994) Low-density lipoprotein as a vehicle for targeting antitumor compounds to cancer cells. Bioconjug Chem 5:105–113. doi:10.1021/bc00026a002
Foucher C, Lagrost L, Maupoil V, Lemeste M, Rochette L, Gambert P (1996) Alterations of lipoprotein fluidity by non-esterified fatty acids known to affect cholesteryl ester transfer protein activity—an electron spin resonance study. Eur J Biochem 236:436–442
Fraley AE, Tsimikas S (2006) Clinical applications of circulating oxidized low-density lipoprotein biomarkers in cardiovascular disease. Curr Opin Lipidol 17:502–509. doi:10.1097/01.mol.0000245255.40634.b5
Frias JC, Lipinski MJ, Lipinski SE, Albelda MT (2007) Modified lipoproteins as contrast agents for imaging of atherosclerosis. Contrast Media Mol Imaging 2:16–23. doi:10.1002/cmmi.124
Galeano NF, Alhaideri M, Keyserman F, Rumsey SC, Deckelbaum RJ (1998) Small dense low density lipoprotein has increased affinity for LDL receptor-independent cell surface binding sites: a potential mechanism for increased atherogenicity. J Lipid Res 39:1263–1273
Gantz DL, Walsh MT, Small DM (2000) Morphology of sodium deoxycholate-solubilized apolipoprotein B-100 using negative stain and vitreous ice electron microscopy. J Lipid Res 41:1464–1472
Goldberg IJ, Wagner WD, Pang L, Paka L, Curtiss LK, DeLozier JA et al (1998) The NH2-terminal region of apolipoprotein B is sufficient for lipoprotein association with glycosaminoglycans. J Biol Chem 273:35355–35361. doi:10.1074/jbc.273.52.35355
Gulik-Krzywicki T, Yates M, Aggerbeck LP (1979) Structure of serum low-density lipoprotein. J Mol Biol 131:475–484. doi:10.1016/0022-2836(79)90003-2
Hammel M, Laggner P, Prassl R (2003) Structural characterisation of nucleoside loaded low density lipoprotein as a main criterion for the applicability as drug delivery system. Chem Phys Lipids 123:193–207. doi:10.1016/S0009-3084(03)00002-1
Hevonoja T, Pentikainen MO, Hyvonen MT, Kovanen PT, Ala-Korpela M (2000) Structure of low density lipoprotein (LDL) particles: basis for understanding molecular changes in modified LDL. Biochim Biophys Acta 1488:189–210
Hokanson JE, Krauss RM, Albers JJ, Austin MA, Brunzell JD (1995) LDL physical and chemical properties in familial combined hyperlipidemia. Arterioscler Thromb Vasc Biol 15:452–459
Hospattankar AV, Law SW, Lackner K, Brewer HB Jr (1986) Identification of low density lipoprotein receptor binding domains of human apolipoprotein B-100: a proposed consensus LDL receptor binding sequence of apoB-100. Biochem Biophys Res Commun 139:1078–1085. doi:10.1016/S0006-291X(86)80287-X
Hurt-Camejo E, Camejo G, Sartipy P (2000) Phospholipase A2 and small, dense low-density lipoprotein. Curr Opin Lipidol 11:465–471. doi:10.1097/00041433-200010000-00004
Hussain MM, Shi J, Dreizen P (2003) Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J Lipid Res 44:22–32. doi:10.1194/jlr.R200014-JLR200
Ikai A (1980) Extraction of the apo B cluster from human low density lipoprotein with Tween 80. J Biochem 88:1349–1357
Ingram MF, Shelness GS (1997) Folding of the amino-terminal domain of apolipoprotein B initiates microsomal triglyceride transfer protein-dependent lipid transfer a to nascent very low density lipoprotein. J Biol Chem 272:10279–10286. doi:10.1074/jbc.272.15.10279
Innerarity TL, Weisgraber KH, Rall SCJ, Mahley RW (1987) Functional domains of apolipoprotein E and apolipoprotein B. Acta Med Scand Suppl 715:51–59
Jiang ZG, Carraway M, McKnight CJ (2005) Limited proteolysis and biophysical characterization of the lipovitellin homology region in apolipoprotein B. Biochemistry 44:1163–1173. doi:10.1021/bi048286y
Jiang ZG, Simon MN, Wall JS, McKnight CJ (2007) Structural analysis of reconstituted lipoproteins containing the N-terminal domain of apolipoprotein B. Biophys J 92:4097–4108. doi:10.1529/biophysj.106.101105
Johs A, Hammel M, Waldner I, May RP, Laggner P, Prassl R (2006) Modular structure of solubilized human apolipoprotein B-100. Low resolution model revealed by small angle neutron scattering. J Biol Chem 281:19732–19739. doi:10.1074/jbc.M601688200
Klein L, Aviram M, Brook GJ, Mokady S, Cogan U (1991) Decreased very low density lipoprotein fluidity in familial hypercholesterolemia. Isr J Med Sci 27:70–74
Knott TJ, Pease RJ, Powell LM, Wallis SC, Rall SC, Innerarity TL et al (1986) Complete protein sequence and identification of structural domains of human apolipoprotein B. Nature 323:734–738. doi:10.1038/323734a0
Kostner GM, Laggner P (1989) Chemical and physical properties of lipoproteins. In: Fruchart JC, Shepherd J (eds) Human plasma lipoproteins—clinical biochemistry, principles, methods, applications. Walter de Gruyter, Berlin, pp 23–54
Kreuzer J, White AL, Knott TJ, Jien ML, Mehrabian M, Scott J et al (1997) Amino terminus of apolipoprotein B suffices to produce recognition of malondialdehyde-modified low density lipoprotein by the scavenger receptor of human monocyte-macrophages. J Lipid Res 38:324–342
Krisko A, Etchebest C (2007) Theoretical model of human apolipoprotein B100 tertiary structure. Proteins 66:342–358. doi:10.1002/prot.21229
Krul ES, Kleinman Y, Kinoshita M, Pfleger B, Oida K, Law A et al (1988) Regional specificities of monoclonal anti-human apolipoprotein B antibodies. J Lipid Res 29:937–947
Kruth HS (1997) The fate of lipoprotein cholesterol entering the arterial wall. Curr Opin Lipidol 8:246–252
Laggner P (1995) X-ray and neutron small-angle scattering on plasma lipoproteins. In: Brumberger H (ed) Modern aspects of small-angle scattering. Kluwer Academic Publishers, The Netherlands, pp 371–386
Laggner P, Kostner GM (1978) Thermotropic changes in the surface structure of lipoprotein B from human-plasma low-density lipoproteins. A spin-label study. Eur J Biochem 84:227–232. doi:10.1111/j.1432-1033.1978.tb12160.x
Laggner P, Müller K (1978) The structure of serum lipoproteins as analysed by X-ray small-angle scattering. Q Rev Biophys 11:371–425
Laggner P, Degovics G, Müller KW, Glatter O, Kostner GM, Holasek A (1977) Molecular packing and fluidity of lipids in human serum low density lipoproteins. Hoppe Seylers Z Physiol Chem 358:771–778
Laggner P, Chapman MJ, Goldstein S (1978) An X-Ray Small-Angle Scattering Study of Trypsin Treated Low Density Lipoprotein from Human Serum. Biochem Biophys Res Commun 82:1332–1339. doi:10.1016/0006-291X(78)90335-2
Laggner P, Kostner GM, Rakusch U, Worcester DL (1981) Neutron small-angle scattering on selectively deuterated human plasma low density lipoproteins. The location of polar phospholipid headgroups. J Biol Chem 256:11832–11839
Laggner P, Kostner GM, Degovics G, Worcester DL (1984) Structure of the cholesteryl ester core of human plasma low density lipoproteins: selective deuteration and neutron small-angle scattering. Proc Natl Acad Sci USA 81:4389–4393. doi:10.1073/pnas.81.14.4389
Law A, Scott J (1990) A cross-species comparison of the apolipoprotein B domain that binds to the LDL receptor. J Lipid Res 31:1109–1120
Li L, Mustafi D, Fu Q, Tereshko V, Chen DL, Tice JD et al (2006) Nanoliter microfluidic hybrid method for simultaneous screening and optimization validated with crystallization of membrane proteins. Proc Natl Acad Sci USA 103:19243–19248. doi:10.1073/pnas.0607502103
Lund-Katz S, Phillips MC (1986) Packing of cholesterol molecules in human low-density lipoprotein. Biochemistry 25:1562–1568. doi:10.1021/bi00355a016
Lund-Katz S, Ibdah JA, Letizia JY, Thomas MT, Phillips MC (1988) A 13C NMR characterization of lysine residues in apolipoprotein B and their role in binding to the low density lipoprotein receptor. J Biol Chem 263:13831–13838
Lund-Katz S, Laplaud PM, Phillips MC, Chapman MJ (1998) Apolipoprotein B-100 conformation and particle surface charge in human LDL subspecies: implication for LDL receptor interaction. Biochemistry 37:12867–12874. doi:10.1021/bi980828m
Lunin VY, Lunina NL, Ritter S, Frey I, Berg A, Diederichs K et al (2001) Low-resolution data analysis for low-density lipoprotein particle. Acta Crystallogr D Biol Crystallogr 57:108–121. doi:10.1107/S0907444900014608
Lusa S, Somerharju P (1998) Degradation of low-density-lipoprotein cholesterol esters by lysosomal lipase in-vitro—effect of core physical state and basis of species selectivity. Biochim Biophys Acta 1389:112–122
Lusis AJ (2000) Atherosclerosis. Nature 407:233–241. doi:10.1038/35025203
Luzzati V, Tardieu A, Aggerbeck LP (1979) Structure of serum low-density lipoprotein. J Mol Biol 131:435–473. doi:10.1016/0022-2836(79)90002-0
Mann CJ, Anderson TA, Read J, Chester SA, Harrison GB, Kochl S et al (1999) The structure of vitellogenin provides a molecular model for the assembly and secretion of atherogenic lipoproteins. J Mol Biol 285:391–408. doi:10.1006/jmbi.1998.2298
Mckeone BJ, Patsch JR, Pownall HJ (1993) Plasma triglycerides determine low-density-lipoprotein composition, physical-properties, and cell-specific binding in cultured-cells. J Clin Invest 91:1926–1933. doi:10.1172/JCI116411
McNamara JR, Small DM, Li ZL, Schaefer EJ (1996) Differences in LDL subspecies involve alterations in lipid composition and conformational changes in apolipoprotein B. J Lipid Res 37:1924–1935
Morrisett JD, Gaubatz JW, Tarver AP, Allen JK, Pownell HJ, Laggner P et al (1984) Thermotropic properties and molecular dynamics of cholesteryl ester rich very low density lipoproteins: effect of hydrophobic core on polar surface. Biochemistry 23:5343–5352. doi:10.1021/bi00317a037
Morton RE, Parks JS (1996) Plasma cholesteryl ester transfer activity is modulated by the phase transition of the lipoprotein core. J Lipid Res 37:1915–1923
Nigon F, Lesnik P, Rouis M, Chapman MJ (1991) Discrete subspecies of human low density lipoproteins are heterogeneous in their interaction with the cellular LDL receptor. J Lipid Res 32:1741–1753
Nikanjam M, Blakely EA, Bjornstad KA, Shu X, Budinger TF, Forte TM (2007a) Synthetic nano-low density lipoprotein as targeted drug delivery vehicle for glioblastoma multiforme. Int J Pharm 328:86–94. doi:10.1016/j.ijpharm.2006.07.046
Nikanjam M, Gibbs AR, Hunt CA, Budinger TF, Forte TM (2007b) Synthetic nano-LDL with paclitaxel oleate as a targeted drug delivery vehicle for glioblastoma multiforme. J Control Release 124:163–171. doi:10.1016/j.jconrel.2007.09.007
Nohammer B, David C, Burghammer M, Riekel C (2005) Coherence-matched microfocusing of hard x rays. Appl Phys Lett 86:163104. doi:10.1063/1.1905782
Orlova EV, Sherman MB, Chiu W, Mowri H, Smith LC, Gotto AM (1999) Three-dimensional structure of low density lipoproteins by electron cryomicroscopy. Proc Natl Acad Sci USA 96:8420–8425. doi:10.1073/pnas.96.15.8420
Packard CJ (2006) Small dense low-density lipoprotein and its role as an independent predictor of cardiovascular disease. Curr Opin Lipidol 17:412–417. doi:10.1097/01.mol.0000236367.42755.c1
Packard C, Caslake M, Shepherd J (2000) The role of small, dense low density lipoprotein (LDL): a new look. Int J Cardiol 74(Suppl 1):S17–S22. doi:10.1016/S0167-5273(99)00107-2
Parks JS, Huggins KW, Gebre AK, Burleson ER (2000) Phosphatidylcholine fluidity and structure affect lecithin:cholesterol acyltransferase activity. J Lipid Res 41:546–553
Pentikainen MO, Oksjoki R, Oorni K, Kovanen PT (2002) Lipoprotein lipase in the arterial wall: linking LDL to the arterial extracellular matrix and much more. Arterioscler Thromb Vasc Biol 22:211–217. doi:10.1161/hq0102.101551
Phillips ML, Schumaker VN (1989) Conformation of apolipoprotein B after lipid extraction of low-density lipoproteins attached to an electron microscope grid. J Lipid Res 30:415–422
Pownall HJ, Shepherd J, Mantulin WW, Sklar LA, Gotto AM (1980) Effect of saturated and polyunsaturated fat diets on the composition and structure of human low-density lipoproteins. Atherosclerosis 36:299–314. doi:10.1016/0021-9150(80)90211-7
Prassl R, Schuster B, Abuja PM, Zechner M, Kostner GM, Laggner P (1995) A comparison of structure and thermal behavior in human plasma lipoprotein(a) and low-density lipoprotein. calorimetry and small-angle x-ray scattering. Biochemistry 34:3795–3801. doi:10.1021/bi00011a037
Prassl R, Chapman JM, Nigon F, Sara M, Eschenburg S, Betzel C et al (1996) Crystallization and preliminary X-ray analysis of a low density lipoprotein from human plasma. J Biol Chem 271:28731–28733. doi:10.1074/jbc.271.46.28731
Prassl R, Hammel M, Laggner P (2006) Small-angle solution scattering of proteins. Recent Adv Res Updates 7:101–112
Pregetter M, Prassl R, Schuster B, Kriechbaum M, Nigon F, Chapman J et al (1999) Microphase separation in low density lipoproteins. Evidence for a fluid triglyceride core below the lipid melting transition. J Biol Chem 274:1334–1341. doi:10.1074/jbc.274.3.1334
Putnam CD, Hammel M, Hura GL, Tainer JA (2007) X-ray solution scattering (SAXS) combined with crystallography and computation: defining accurate macromolecular structures, conformations and assemblies in solution. Q Rev Biophys 40:191–285. doi:10.1017/S0033583507004635
Rensen PC, de Vrueh RL, Kuiper J, Bijsterbosch MK, Biessen EA, van Berkel TJ (2001) Recombinant lipoproteins: lipoprotein-like lipid particles for drug targeting. Adv Drug Deliv Rev 47:251–276. doi:10.1016/S0169-409X(01)00109-0
Ritter S, Frey I, Diederichs K, Grathwohl D, Keul J, Baumstark MW (1997) Crystallization and preliminary X-ray diffraction data of two different human low-density lipoprotein (LDL) subfractions. Proteins 28:293–297. doi:10.1002/(SICI)1097-0134(199706)28:2<293::AID-PROT17>3.0.CO;2-D
Sali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234:779–815. doi:10.1006/jmbi.1993.1626
Schumaker VN, Phillips ML, Chatterton JE (1994) Apolipoprotein B and low-density lipoprotein structure: implications for biosynthesis of triglyceride-rich lipoproteins. Adv Protein Chem 45:205–248. doi:10.1016/S0065-3233(08)60641-5
Schuster B, Prassl R, Nigon F, Chapman MJ, Laggner P (1995) Core lipid structure is a major determinant of the oxidative resistance of low density lipoprotein. Proc Natl Acad Sci USA 92:2509–2513. doi:10.1073/pnas.92.7.2509
Segrest JP, Jones MK, Mishra VK, Anantharamaiah GM, Garber DW (1994) ApoB-100 has a pentapartite structure composed of three amphipathic α-helical domains alternating with two amphipathic β-strand domains. Arterioscler Thromb 14:1674–1685
Segrest JP, Jones MK, Dashti N (1999) N-terminal domain of apolipoprotein B has structural homology to lipovitellin and microsomal triglyceride transfer protein: a ‘‘lipid pocket’’ model for self- assembly of apoB-containing lipoprotein particles. J Lipid Res 40:1401–1416
Segrest JP, Jones MK, De Loof H, Dashti N (2001) Structure of apolipoprotein B-100 in low density lipoproteins. J Lipid Res 42:1346–1367
Shelness GS, Hou L, Ledford AS, Parks JS, Weinberg RB (2003) Identification of the lipoprotein initiating domain of apolipoprotein B. J Biol Chem 278:44702–44707. doi:10.1074/jbc.M307562200
Sherman MB, Orlova EV, Decker GL, Chiu W, Pownall HJ (2003) Structure of triglyceride-rich human low-density lipoproteins according to cryoelectron microscopy. Biochemistry 42:14988–14993. doi:10.1021/bi0354738
Sivaram P, Choi SY, Curtiss LK, Goldberg IJ (1994) An amino-terminal fragment of apolipoprotein B binds to lipoprotein lipase and may facilitate its binding to endothelial cells. J Biol Chem 269:9409–9412
Skalen K, Gustafsson M, Rydberg EK, Hulten LM, Wiklund O, Innerarity TL et al (2002) Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature 417:750–754. doi:10.1038/nature00804
Sommer A, Prenner E, Gorges R, Stütz H, Grillhofer H, Kostner GM, Paltauf F, Hermetter A (1992) Organization of phosphatidylcholine and sphingomyelin in the surface monolayer of low density lipoprotein and lipoprotein(a) as determined by time-resolved fluorometry. J Biol Chem 267:24217–24222
Sorzano CO, Jonic S, Cottevieille M, Larquet E, Boisset N, Marco S (2007) 3D electron microscopy of biological nanomachines: principles and applications. Eur Biophys J 36:995–1013. doi:10.1007/s00249-007-0203-x
Spin JM, Atkinson D (1995) Cryoelectron microscopy of low density lipoprotein in vitreous ice. Biophys J 68:2115–2123
Steinberg D, Parthasarathy S, Carew S, Khoo JC, Witztum JL (1989) Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 320:915–924
Swaminathan N, Aladjem F (1976) The monosaccharide composition and sequence of the carbohydrate moiety of human serum low density lipoproteins. Biochemistry 15:1516. doi:10.1021/bi00652a024
Teng B, Sniderman A, Krauss RM, Kwiterovich PO, Milne RW, Marcel YL (1985) Modulation of apolipoprotein B antigenic determinants in human low density lipoprotein subclasses. J Biol Chem 260:5067–5072
Tran K, Boren J, Macri J, Wang YW, Mcleod R, Avramoglu RK et al (1998) Functional analysis of disulfide linkages clustered within the amino terminus of human apolipoprotein b. J Biol Chem 273:7244–7251. doi:10.1074/jbc.273.13.7244
Tribet C, Audebert R, Popot JL (1996) Amphipols - Polymers that keep membrane-proteins soluble in aqueous-solutions. Proc Natl Acad Sci USA 93:15047–15050. doi:10.1073/pnas.93.26.15047
Tribet C, Audebert R, Popot JL (1997) Stabilization of hydrophobic colloidal dispersions in water with amphiphilic polymers: application to integral membrane proteins. Langmuir 13:5570–5576. doi:10.1021/la970136j
Van Antwerpen R (2004) Preferred orientations of LDL in vitreous ice indicate a discoid shape of the lipoprotein particle. Arch Biochem Biophys 432:122–127
Van Antwerpen R, Chen GC, Pullinger CR, Kane JP, Labelle M, Krauss RM et al (1997) Cryo-electron microscopy of low density lipoprotein and reconstituted discoidal high density lipoprotein: imaging of the apolipoprotein moiety. J Lipid Res 38:659–669
Vauhkonen M, Somerharju P (1989) Parinoroyl and pyrenyl phospholipids as probes for the lipid surface layer of human low density lipoproteins. Biochim Biophys Acta 984:81–87. doi:10.1016/0005-2736(89)90345-3
Walsh MT, Atkinson D (1983) Sobulization of low-density lipoprotein with sodium deoxycholate and recombination of apolipoprotein B with dimyristoylphosphatidylcholine. Biochemistry 22:3170–3178. doi:10.1021/bi00282a021
Walsh MT, Atkinson D (1986) Physical properties of apoprotein B in mixed micelles with sodium deoxycholate and in a vesicle with dimyristoyl phosphatidylcholine. J Lipid Res 27:316–325
Walsh MT, Atkinson D (1990) Calorimetric and spectroscopic investigation of the unfolding of human apolipoprotein B. J Lipid Res 31:1051–1062
Wang L, Walsh MT, Small DM (2006) Apolipoprotein B is conformationally flexible but anchored at a triolein/water interface: a possible model for lipoprotein surfaces. Proc Natl Acad Sci USA 103:6871–6876. doi:10.1073/pnas.0602213103
Williams KJ, Tabas I (2005) Lipoprotein retention–and clues for atheroma regression. Arterioscler Thromb Vasc Biol 25:1536–1540. doi:10.1161/01.ATV.0000174795.62387.d3
Yang S, Zhang S (2006) Self-assembling behavior of designer lipid-like peptides. Supramolecular Chem 18:289–396
Yang C-Y, Chen S-H, Gianturco SH, Bradley WA, Sparrow JT, Tanimura M et al (1986) Sequence, structure, receptor-binding domains and internal repeats of human apolipoprotein B-100. Nature 323:738–742. doi:10.1038/323738a0
Yang CY, Kim TW, Pao Q, Chan L, Knapp RD, Gotto AM Jr et al (1989) Structure and conformational analysis of lipid-associating peptides of apolipoprotein B-100 produced by trypsinolysis. J Protein Chem 8:689–699. doi:10.1007/BF01024895
Yeagle PL, Langdon RG, Martin RB (1977) Phospholipid-protein interactions in human low density lipoprotein detected by 31P nuclear magnetic resonance. Biochemistry 16:3487–3491. doi:10.1021/bi00634a031
Zampighi G, Reynolds JA, Watt RM (1980) Characterization of apolipoprotein B from human serum low density lipoprotein in n-dodecyl octaethyleneglycol monoether: an electron microscope study. J Cell Biol 87:555–561. doi:10.1083/jcb.87.3.555
Zechner R, Kostner GM, Dieplinger H, Degovics G, Laggner P (1984) In vitro modification of the chemical composition of human plasma low-density lipoproteins: Effects on morphology and thermal properties. Chem Phys Lipids 36:111–119. doi:10.1016/0009-3084(84)90064-1
Zhao X, Nagai Y, Reeves PJ, Kiley P, Khorana HG, Zhang S (2006) Designer short peptide surfactants stabilize G protein-coupled receptor bovine rhodopsin. Proc Natl Acad Sci USA 103:17707–17712. doi:10.1073/pnas.0607167103
Zheng G, Chen J, Li H, Glickson JD (2005) Rerouting lipoprotein nanoparticles to selected alternate receptors for the targeted delivery of cancer diagnostic and therapeutic agents. Proc Natl Acad Sci USA 102:17757–17762. doi:10.1073/pnas.0508677102
Acknowledgments
The work was supported by the Austrian Science Funds (P16479 and P20455 apart from Seegen Stiftung of the Austrian Acad Sci.). The author would like to thank Heinz Amenitsch and Manfred Kriechbaum for scientific support in SAXS experiments and Christopher Wrighton for text editing.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Prassl, R., Laggner, P. Molecular structure of low density lipoprotein: current status and future challenges. Eur Biophys J 38, 145–158 (2009). https://doi.org/10.1007/s00249-008-0368-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00249-008-0368-y