Review
Using Sterol Substitution to Probe the Role of Membrane Domains in Membrane Functions
JiHyun Kim,
Erwin London,
JiHyun Kim
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, 11794-5215 USA
Search for more papers by this authorCorresponding Author
Erwin London
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, 11794-5215 USA
Search for more papers by this author
JiHyun Kim,
Erwin London,
JiHyun Kim
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, 11794-5215 USA
Search for more papers by this authorCorresponding Author
Erwin London
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, 11794-5215 USA
Search for more papers by this authorPart of the topical collection G. J. Schroepfer, Jr. Memorial Sterol Symposium.
Abstract
Ordered membrane lipid domains rich in sphingolipids and sterols (“lipid rafts”) are thought to be important in many biological processes. However, it is often difficult to distinguish domain-dependent biological functions from ones that have a specific dependence on sterol, e.g. are dependent upon a protein with a function that is dependent upon its binding to sterol. Removing cholesterol and replacing it with various sterols with varying abilities to form membrane domains or otherwise alter membrane properties has the potential to help distinguish these cases. This review describes this strategy, and how it has been applied by various investigators to understand cellular functions.
References
- 1Brown DA, London E (1998) Structure and origin of ordered lipid domains in biological membranes. J Membr Biol 164(2): 103–114
10.1007/s002329900397 Google Scholar
- 2Schroeder R, London E, Brown D (1994) Interactions between saturated acyl chains confer detergent resistance on lipids and glycosylphosphatidylinositol (GPI)-anchored proteins: GPI-anchored proteins in liposomes and cells show similar behavior. Proc Natl Acad Sci USA 91(25): 12130–12134
10.1073/pnas.91.25.12130 Google Scholar
- 3Simons K, Ikonen E (1997) Functional rafts in cell membranes. Nature 387(6633): 569–572
- 4Ahmed SN, Brown DA, London E (1997) On the origin of sphingolipid/cholesterol-rich detergent-insoluble cell membranes: physiological concentrations of cholesterol and sphingolipid induce formation of a detergent-insoluble, liquid-ordered lipid phase in model membranes. Biochemistry 36(36): 10944–10953
- 5Brown DA, London E (1998) Functions of lipid rafts in biological membranes. Annu Rev Cell Dev Biol 14: 111–136
- 6Head BP, Patel HH, Insel PA (2014) Interaction of membrane/lipid rafts with the cytoskeleton: impact on signaling and function: membrane/lipid rafts, mediators of cytoskeletal arrangement and cell signaling. Biochim Biophys Acta 1838(2): 532–545
- 7Lafont F et al (2002) Initial steps of Shigella infection depend on the cholesterol/sphingolipid raft-mediated CD44–IpaB interaction. EMBO J 21(17): 4449–4457
- 8Baorto DM et al (1997) Survival of FimH-expressing enterobacteria in macrophages relies on glycolipid traffic. Nature 389(6651): 636–639
10.1038/39376 Google Scholar
- 9Duncan MJ et al (2004) Bacterial penetration of bladder epithelium through lipid rafts. J Biol Chem 279(18): 18944–18951
10.1074/jbc.M400769200 Google Scholar
- 10Konkel ME et al (1992) Characteristics of the internalization and intracellular survival of Campylobacter jejuni in human epithelial cell cultures. Microb Pathog 13(5): 357–370
- 11Seveau S et al (2004) Role of lipid rafts in E-cadherin—and HGF-R/Met—mediated entry of Listeria monocytogenes into host cells. J Cell Biol 166(5): 743–753
- 12Simons K, Sampaio JL (2011) Membrane organization and lipid rafts. Cold Spring Harb Perspect Biol 3(10): a004697
- 13Brown DA (2006) Lipid rafts, detergent-resistant membranes, and raft targeting signals. Physiology (Bethesda) 21: 430–439
- 14Lingwood D, Simons K (2010) Lipid rafts as a membrane-organizing principle. Science 327(5961): 46–50
- 15Campbell SM, Crowe SM, Mak J (2001) Lipid rafts and HIV-1: from viral entry to assembly of progeny virions. J Clin Virol 22(3): 217–227
10.1016/S1386-6532(01)00193-7 Google Scholar
- 16LaRocca TJ et al (2010) Cholesterol lipids of Borrelia burgdorferi form lipid rafts and are required for the bactericidal activity of a complement-independent antibody. Cell Host Microbe 8(4): 331–342
- 17LaRocca TJ et al (2013) Proving lipid rafts exist: membrane domains in the prokaryote Borrelia burgdorferi have the same properties as eukaryotic lipid rafts. PLoS Pathog 9(5): e1003353
- 18Toulmay A, Prinz WA (2013) Direct imaging reveals stable, micrometer-scale lipid domains that segregate proteins in live cells. J Cell Biol 202(1): 35–44
- 19Gaus K, Zech T, Harder T (2006) Visualizing membrane microdomains by Laurdan 2-photon microscopy. Mol Membr Biol 23(1): 41–48
- 20Petruzielo RS et al (2013) Phase behavior and domain size in sphingomyelin-containing lipid bilayers. Biochim Biophys Acta 1828(4): 1302–1313
10.1016/j.bbamem.2013.01.007 Google Scholar
- 21Pathak P, London E (2011) Measurement of lipid nanodomain (raft) formation and size in sphingomyelin/POPC/cholesterol vesicles shows TX-100 and transmembrane helices increase domain size by coalescing preexisting nanodomains but do not induce domain formation. Biophys J 101(10): 2417–2425
10.1016/j.bpj.2011.08.059 Google Scholar
- 22Brown DA, Rose JK (1992) Sorting of GPI-anchored proteins to glycolipid-enriched membrane subdomains during transport to the apical cell surface. Cell 68(3): 533–544
- 23Brown DA, London E (2000) Structure and function of sphingolipid- and cholesterol-rich membrane rafts. J Biol Chem 275(23): 17221–17224
- 24Heerklotz H (2002) Triton promotes domain formation in lipid raft mixtures. Biophys J 83(5): 2693–2701
- 25London E, Brown DA (2000) Insolubility of lipids in triton X-100: physical origin and relationship to sphingolipid/cholesterol membrane domains (rafts). Biochim Biophys Acta 1508(1–2): 182–195
10.1016/S0304-4157(00)00007-1 Google Scholar
- 26London E (2005) How principles of domain formation in model membranes may explain ambiguities concerning lipid raft formation in cells. Biochim Biophys Acta 1746(3): 203–220
10.1016/j.bbamcr.2005.09.002 Google Scholar
- 27Zidovetzki R, Levitan I (2007) Use of cyclodextrins to manipulate plasma membrane cholesterol content: evidence, misconceptions and control strategies. Biochim Biophys Acta 1768(6): 1311–1324
- 28Xu X, London E (2000) The effect of sterol structure on membrane lipid domains reveals how cholesterol can induce lipid domain formation. Biochemistry 39(5): 843–849
- 29Holz RW (1974) The effects of the polyene antibiotics nystatin and amphotericin B on thin lipid membranes. Ann NY Acad Sci 235: 469–479
- 30Dahl JS, Dahl CE, Bloch K (1980) Sterols in membranes: growth characteristics and membrane properties of Mycoplasma capricolum cultured on cholesterol and lanosterol. Biochemistry 19(7): 1467–1472
10.1021/bi00548a032 Google Scholar
- 31Dahl CE, Dahl JS, Bloch K (1980) Effect of alkyl-substituted precursors of cholesterol on artificial and natural membranes and on the viability of Mycoplasma capricolum. Biochemistry 19(7): 1462–1467
10.1021/bi00548a031 Google Scholar
- 32Dahl JS, Dahl CE, Bloch K (1981) Effect of cholesterol on macromolecular synthesis and fatty acid uptake by Mycoplasma capricolum. J Biol Chem 256(1): 87–91
- 33Dahl JS, Dahl CE, Bloch K (1982) Role of membrane sterols in Mycoplasma capricolum. Rev Infect Dis 4(Suppl): S93–S96
10.1093/clinids/4.Supplement_1.S93 Google Scholar
- 34Odriozola JM et al (1978) Sterol requirement of Mycoplasma capricolum. Proc Natl Acad Sci USA 75(9): 4107–4109
10.1073/pnas.75.9.4107 Google Scholar
- 35Levitan I, Singh DK, Rosenhouse-Dantsker A (2014) Cholesterol binding to ion channels. Front Physiol 5: 65
- 36Kilsdonk EP et al (1995) Cellular cholesterol efflux mediated by cyclodextrins. J Biol Chem 270(29): 17250–17256
10.1074/jbc.270.29.17250 Google Scholar
- 37Yancey PG et al (1996) Cellular cholesterol efflux mediated by cyclodextrins. Demonstration of kinetic pools and mechanism of efflux. J Biol Chem 271(27): 16026–16034
- 38Atger VM et al (1997) Cyclodextrins as catalysts for the removal of cholesterol from macrophage foam cells. J Clin Invest 99(4): 773–780
- 39Wang J, Megha, London E (2004) Relationship between sterol/steroid structure and participation in ordered lipid domains (lipid rafts): implications for lipid raft structure and function. Biochemistry 43(4): 1010–1018
- 40Xu X et al (2001) Effect of the structure of natural sterols and sphingolipids on the formation of ordered sphingolipid/sterol domains (rafts). Comparison of cholesterol to plant, fungal, and disease-associated sterols and comparison of sphingomyelin, cerebrosides, and ceramide. J Biol Chem 276(36): 33540–33546
10.1074/jbc.M104776200 Google Scholar
- 41Wenz JJ, Barrantes FJ (2003) Steroid structural requirements for stabilizing or disrupting lipid domains. Biochemistry 42(48): 14267–14276
10.1021/bi035759c Google Scholar
- 42Beattie ME et al (2005) Sterol structure determines miscibility versus melting transitions in lipid vesicles. Biophys J 89(3): 1760–1768
10.1529/biophysj.104.049635 Google Scholar
- 43Westover EJ, Covey DF (2004) The enantiomer of cholesterol. J Membr Biol 202(2): 61–72
- 44Bang B, Gniadecki R, Gajkowska B (2005) Disruption of lipid rafts causes apoptotic cell death in HaCaT keratinocytes. Exp Dermatol 14(4): 266–272
- 45Gniadecki R (2004) Depletion of membrane cholesterol causes ligand-independent activation of Fas and apoptosis. Biochem Biophys Res Commun 320(1): 165–169
- 46Bakht O, Pathak P, London E (2007) Effect of the structure of lipids favoring disordered domain formation on the stability of cholesterol-containing ordered domains (lipid rafts): identification of multiple raft-stabilization mechanisms. Biophys J 93(12): 4307–4318
10.1529/biophysj.107.114967 Google Scholar
- 47Sengupta P, Holowka D, Baird B (2007) Fluorescence resonance energy transfer between lipid probes detects nanoscopic heterogeneity in the plasma membrane of live cells. Biophys J 92(10): 3564–3574
10.1529/biophysj.106.094730 Google Scholar
- 48Nelson LD, Johnson AE, London E (2008) How interaction of perfringolysin O with membranes is controlled by sterol structure, lipid structure, and physiological low pH: insights into the origin of perfringolysin O–lipid raft interaction. J Biol Chem 283(8): 4632–4642
- 49Lin Q, London E (2013) Transmembrane protein (perfringolysin O) association with ordered membrane domains (rafts) depends upon the raft-associating properties of protein-bound sterol. Biophys J 105(12): 2733–2742
- 50Phalen T, Kielian M (1991) Cholesterol is required for infection by Semliki Forest virus. J Cell Biol 112(4): 615–623
10.1083/jcb.112.4.615 Google Scholar
- 51Okamoto Y et al (2000) Cholesterol oxidation switches the internalization pathway of endothelin receptor type A from caveolae to clathrin-coated pits in Chinese hamster ovary cells. J Biol Chem 275(9): 6439–6446
10.1074/jbc.275.9.6439 Google Scholar
- 52Pucadyil TJ, Chattopadhyay A (2004) Cholesterol modulates ligand binding and G-protein coupling to serotonin (1A) receptors from bovine hippocampus. Biochim Biophys Acta 1663(1–2): 188–200
- 53Pucadyil TJ, Shrivastava S, Chattopadhyay A (2005) Membrane cholesterol oxidation inhibits ligand binding function of hippocampal serotonin (1A) receptors. Biochem Biophys Res Commun 331(2): 422–427
10.1016/j.bbrc.2005.03.178 Google Scholar
- 54Rouquette-Jazdanian AK et al (2006) Revaluation of the role of cholesterol in stabilizing rafts implicated in T cell receptor signaling. Cell Signal 18(1): 105–122
10.1016/j.cellsig.2005.03.024 Google Scholar
- 55Klink M et al (2013) Cholesterol oxidase is indispensable in the pathogenesis of Mycobacterium tuberculosis. PLoS One 8(9): e73333
10.1371/journal.pone.0073333 Google Scholar
- 56Neuvonen M et al (2014) Enzymatic oxidation of cholesterol: properties and functional effects of cholestenone in cell membranes. PLoS One 9(8): e103743
10.1371/journal.pone.0103743 Google Scholar
- 57Campbell S et al (2004) The raft-promoting property of virion-associated cholesterol, but not the presence of virion-associated Brij 98 rafts, is a determinant of human immunodeficiency virus type 1 infectivity. J Virol 78(19): 10556–10565
10.1128/JVI.78.19.10556-10565.2004 Google Scholar
- 58Gimpl G, Burger K, Fahrenholz F (1997) Cholesterol as modulator of receptor function. Biochemistry 36(36): 10959–10974
10.1021/bi963138w Google Scholar
- 59Klein U, Gimpl G, Fahrenholz F (1995) Alteration of the myometrial plasma membrane cholesterol content with beta-cyclodextrin modulates the binding affinity of the oxytocin receptor. Biochemistry 34(42): 13784–13793
- 60Pang L, Graziano M, Wang S (1999) Membrane cholesterol modulates galanin–GalR2 interaction. Biochemistry 38(37): 12003–12011
10.1021/bi990227a Google Scholar
- 61Papanikolaou A et al (2005) Cholesterol-dependent lipid assemblies regulate the activity of the ecto-nucleotidase CD39. J Biol Chem 280(28): 26406–26414
- 62Singh P et al (2009) Differential effects of cholesterol and desmosterol on the ligand binding function of the hippocampal serotonin (1A) receptor: implications in desmosterolosis. Biochim Biophys Acta 1788(10): 2169–2173
10.1016/j.bbamem.2009.07.004 Google Scholar
- 63Westover EJ et al (2003) Cholesterol depletion results in site-specific increases in epidermal growth factor receptor phosphorylation due to membrane level effects. Studies with cholesterol enantiomers. J Biol Chem 278(51): 51125–51133
- 64Yamamoto M et al (2011) Structural requirements of virion-associated cholesterol for infectivity, buoyant density and apolipoprotein association of hepatitis C virus. J Gen Virol 92(Pt 9): 2082–2087
10.1099/vir.0.032391-0 Google Scholar
- 65Romanenko VG et al (2009) The role of cell cholesterol and the cytoskeleton in the interaction between IK1 and maxi-K channels. Am J Physiol Cell Physiol 296(4): C878–C888
10.1152/ajpcell.00438.2008 Google Scholar
- 66Romanenko VG, Rothblat GH, Levitan I (2002) Modulation of endothelial inward-rectifier K+ current by optical isomers of cholesterol. Biophys J 83(6): 3211–3222
- 67Romanenko VG, Rothblat GH, Levitan I (2004) Sensitivity of volume-regulated anion current to cholesterol structural analogues. J Gen Physiol 123(1): 77–87
10.1085/jgp.200308882 Google Scholar
- 68Wang J, Wu F, Shi C (2013) Substitution of membrane cholesterol with beta-sitosterol promotes nonamyloidogenic cleavage of endogenous amyloid precursor protein. Neuroscience 247: 227–233
- 69Sooksawate T, Simmonds MA (2001) Influence of membrane cholesterol on modulation of the GABA(A) receptor by neuroactive steroids and other potentiators. Br J Pharmacol 134(6): 1303–1311
- 70Sooksawate T, Simmonds MA (2001) Effects of membrane cholesterol on the sensitivity of the GABA(A) receptor to GABA in acutely dissociated rat hippocampal neurones. Neuropharmacology 40(2): 178–184
10.1016/S0028-3908(00)00159-3 Google Scholar
- 71Brown AJ et al (2002) Cholesterol addition to ER membranes alters conformation of SCAP, the SREBP escort protein that regulates cholesterol metabolism. Mol Cell 10(2): 237–245
- 72Picazo-Juarez G et al (2011) Identification of a binding motif in the S5 helix that confers cholesterol sensitivity to the TRPV1 ion channel. J Biol Chem 286(28): 24966–24976
- 73Rentero C et al (2008) Functional implications of plasma membrane condensation for T cell activation. PLoS One 3(5): e2262
10.1371/journal.pone.0002262 Google Scholar
- 74Byfield FJ et al (2006) Evidence for the role of cell stiffness in modulation of volume-regulated anion channels. Acta Physiol (Oxf) 187(1–2): 285–294
- 75Fahrenholz F, Klein U, Gimpl G (1995) Conversion of the myometrial oxytocin receptor from low to high affinity state by cholesterol. Adv Exp Med Biol 395: 311–319
- 76Cross NL (1996) Effect of cholesterol and other sterols on human sperm acrosomal responsiveness. Mol Reprod Dev 45(2): 212–217
- 77Cross NL (1999) Effect of methyl-beta-cyclodextrin on the acrosomal responsiveness of human sperm. Mol Reprod Dev 53(1): 92–98
- 78Nimmo MR, Cross NL (2003) Structural features of sterols required to inhibit human sperm capacitation. Biol Reprod 68(4): 1308–1317
10.1095/biolreprod.102.008607 Google Scholar
- 79Brown MS, Goldstein JL (1999) A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc Natl Acad Sci USA 96(20): 11041–11048
- 80DeBose-Boyd RA et al (1999) Transport-dependent proteolysis of SREBP: relocation of site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi. Cell 99(7): 703–712
- 81Goldstein JL, Rawson RB, Brown MS (2002) Mutant mammalian cells as tools to delineate the sterol regulatory element-binding protein pathway for feedback regulation of lipid synthesis. Arch Biochem Biophys 397(2): 139–148
10.1006/abbi.2001.2615 Google Scholar
- 82Nohturfft A et al (2000) Regulated step in cholesterol feedback localized to budding of SCAP from ER membranes. Cell 102(3): 315–323
10.1016/S0092-8674(00)00037-4 Google Scholar
- 83Dykstra M et al (2003) Location is everything: lipid rafts and immune cell signaling. Annu Rev Immunol 21: 457–481
- 84Gaus K et al (2005) Condensation of the plasma membrane at the site of T lymphocyte activation. J Cell Biol 171(1): 121–131
- 85Singh P et al (2011) Desmosterol replaces cholesterol for ligand binding function of the serotonin (1A) receptor in solubilized hippocampal membranes: support for nonannular binding sites for cholesterol? Biochim Biophys Acta 1808(10): 2428–2434
10.1016/j.bbamem.2011.06.022 Google Scholar
- 86Goodenough S, Schafer M, Behl C (2003) Estrogen-induced cell signalling in a cellular model of Alzheimer's disease. J Steroid Biochem Mol Biol 84(2–3): 301–305
10.1016/S0960-0760(03)00043-8 Google Scholar
- 87Huang Z, London E (2013) Effect of cyclodextrin and membrane lipid structure upon cyclodextrin–lipid interaction. Langmuir 29(47): 14631–14638
10.1021/la4031427 Google Scholar
- 88Stubs G et al (2009) Acylated cholesteryl galactosides are specific antigens of borrelia causing lyme disease and frequently induce antibodies in late stages of disease. J Biol Chem 284(20): 13326–13334
- 89Simon-Plas F et al (2011) An update on plant membrane rafts. Curr Opin Plant Biol 14(6): 642–649
10.1016/j.pbi.2011.08.003 Google Scholar
- 90Sunshine C, McNamee MG (1994) Lipid modulation of nicotinic acetylcholine receptor function: the role of membrane lipid composition and fluidity. Biochim Biophys Acta 1191(1): 59–64
10.1016/0005-2736(94)90233-X Google Scholar
- 91Addona GH et al (2003) Low chemical specificity of the nicotinic acetylcholine receptor sterol activation site. Biochim Biophys Acta 1609(2): 177–182
10.1016/S0005-2736(02)00685-5 Google Scholar
- 92Fong TM, McNamee MG (1986) Correlation between acetylcholine receptor function and structural properties of membranes. Biochemistry 25(4): 830–840
10.1021/bi00352a015 Google Scholar
- 93Singh DK et al (2009) Direct regulation of prokaryotic Kir channel by cholesterol. J Biol Chem 284(44): 30727–30736
- 94Bukiya AN et al (2011) Specificity of cholesterol and analogs to modulate BK channels points to direct sterol–channel protein interactions. J Gen Physiol 137(1): 93–110
10.1085/jgp.201010519 Google Scholar
- 95Razinkov VI, Cohen FS (2000) Sterols and sphingolipids strongly affect the growth of fusion pores induced by the hemagglutinin of influenza virus. Biochemistry 39(44): 13462–13468
10.1021/bi0012078 Google Scholar
- 96Popot JL et al (1978) Interaction of the acetylcholine (nicotinic) receptor protein from Torpedo marmorata electric organ with monolayers of pure lipids. Eur J Biochem 85(1): 27–42
- 97Vitrac H, Bogdanov M, Dowhan W (2013) In vitro reconstitution of lipid-dependent dual topology and post assembly topological switching of a membrane protein. Proc Natl Acad Sci USA 110(23): 9338–9343
10.1073/pnas.1304375110 Google Scholar
