Cholesterol-Recognition Motifs in Membrane Proteins

  • Jacques Fantini
  • Richard M. Epand
  • Francisco J. Barrantes
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1135)


The impact of cholesterol on the structure and function of membrane proteins was recognized several decades ago, but the molecular mechanisms underlying these effects have remained elusive. There appear to be multiple mechanisms by which cholesterol interacts with proteins. A complete understanding of cholesterol-sensing motifs is still undergoing refinement. Initially, cholesterol was thought to exert only non-specific effects on membrane fluidity. It was later shown that this lipid could specifically interact with membrane proteins and affect both their structure and function. In this article, we have summarized and critically analyzed our evolving understanding of the affinity, specificity and stereoselectivity of the interactions of cholesterol with membrane proteins. We review the different computational approaches that are currently used to identify cholesterol binding sites in membrane proteins and the biochemical logic that governs each type of site, including CRAC, CARC, SSD and amphipathic helix motifs. There are physiological implications of these cholesterol-recognition motifs for G-protein coupled receptors (GPCR) and ion channels, in membrane trafficking and membrane fusion (SNARE) proteins. There are also pathological implications of cholesterol binding to proteins involved in neurological disorders (Alzheimer, Parkinson, Creutzfeldt-Jakob) and HIV fusion. In each case, our discussion is focused on the key molecular aspects of the cholesterol and amino acid motifs in membrane-embedded regions of membrane proteins that define the physiologically relevant crosstalk between the two. Our understanding of the factors that determine if these motifs are functional in cholesterol binding will allow us enhanced predictive capabilities.


Cholesterol Binding site Membrane protein Membrane fusion Virus fusion Neurological disease 


  1. 1.
    Kimura T, Jennings W, Epand RM. Roles of specific lipid species in the cell and their molecular mechanism. Prog Lipid Res. 2016;62:75–92.CrossRefPubMedGoogle Scholar
  2. 2.
    Fantini J, Garmy N, Mahfoud R, Yahi N. Lipid rafts: structure, function and role in HIV, Alzheimer’s and prion diseases. Expert Rev Mol Med. 2002;4:1–22.CrossRefPubMedGoogle Scholar
  3. 3.
    Yang ST, Kreutzberger AJB, Lee J, Kiessling V, Tamm LK. The role of cholesterol in membrane fusion. Chem Phys Lipids. 2016;199:136–43.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Howe V, Sharpe LJ, Alexopoulos SJ, Kunze SV, Chua NK, Li D, Brown AJ. Cholesterol homeostasis: how do cells sense sterol excess? Chem Phys Lipids. 2016;199:170–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Jafurulla M, Chattopadhyay A. Structural stringency of cholesterol for membrane protein function utilizing stereoisomers as novel tools: a review. In: Gelissen IC, Brown AJ, editors. Cholesterol homeostasis: methods and protocols. New York, NY: Springer; 2017. p. 21–39.CrossRefGoogle Scholar
  6. 6.
    Epand RM, Rychnovsky SD, Belani JD, Epand RF. Role of chirality in peptide-induced formation of cholesterol-rich domains. Biochem J. 2005;390:541–8.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Sodt AJ, Sandar ML, Gawrisch K, Pastor RW, Lyman E. The molecular structure of the liquid-ordered phase of lipid bilayers. J Am Chem Soc. 2014;136:725–32.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Gater DL, Saurel O, Iordanov I, Liu W, Cherezov V, Milon A. Two classes of cholesterol binding sites for the beta2AR revealed by thermostability and NMR. Biophys J. 2014;107:2305–12.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Rouviere E, Arnarez C, Yang L, Lyman E. Identification of two new cholesterol interaction sites on the A2A adenosine receptor. Biophys J. 2017;113:2415–24.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Byrne EFX, Sircar R, Miller PS, Hedger G, Luchetti G, Nachtergaele S, Tully MD, Mydock-McGrane L, Covey DF, Rambo RP, et al. Structural basis of smoothened regulation by its extracellular domains. Nature. 2016;535:517–22.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Posada IM, Fantini J, Contreras FX, Barrantes F, Alonso A, Goni FM. A cholesterol recognition motif in human phospholipid scramblase 1. Biophys J. 2014;107:1383–92.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Fantini J, Di Scala C, Baier CJ, Barrantes FJ. Molecular mechanisms of protein-cholesterol interactions in plasma membranes: functional distinction between topological (tilted) and consensus (CARC/CRAC) domains. Chem Phys Lipids. 2016;199:52–60.CrossRefPubMedGoogle Scholar
  13. 13.
    Fantini J, Barrantes FJ. How cholesterol interacts with membrane proteins: an exploration of cholesterol-binding sites including CRAC, CARC, and tilted domains. Front Physiol. 2013;4:31.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Rosenhouse-Dantsker A, Noskov S, Durdagi S, Logothetis DE, Levitan I. Identification of novel cholesterol-binding regions in Kir2 channels. J Biol Chem. 2013;288:31154–64.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Hanson MA, Cherezov V, Griffith MT, Roth CB, Jaakola VP, Chien EY, Velasquez J, Kuhn P, Stevens RC. A specific cholesterol binding site is established by the 2.8 A structure of the human beta2-adrenergic receptor. Structure. 2008;16:897–905.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Fantini J, Di Scala C, Evans LS, Williamson PT, Barrantes FJ. A mirror code for protein-cholesterol interactions in the two leaflets of biological membranes. Sci Rep. 2016;6:21907.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Jaremko L, Jaremko M, Giller K, Becker S, Zweckstetter M. Structure of the mitochondrial translocator protein in complex with a diagnostic ligand. Science. 2014;343:1363–6.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Li H, Papadopoulos V. Peripheral-type benzodiazepine receptor function in cholesterol transport. Identification of a putative cholesterol recognition/interaction amino acid sequence and consensus pattern. Endocrinology. 1998;139:4991–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Baier CJ, Fantini J, Barrantes FJ. Disclosure of cholesterol recognition motifs in transmembrane domains of the human nicotinic acetylcholine receptor. Sci Rep. 2011;1:69.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Palmer M. Cholesterol and the activity of bacterial toxins. FEMS Microbiol Lett. 2004;238:281–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Nishio M, Umezawa Y, Fantini J, Weiss MS, Chakrabarti P. CH-pi hydrogen bonds in biological macromolecules. Phys Chem Chem Phys. 2014;16:12648–83.CrossRefPubMedGoogle Scholar
  22. 22.
    Lee AG. Lipid-protein interactions in biological membranes: a structural perspective. Biochim Biophys Acta. 2003;1612:1–40.CrossRefPubMedGoogle Scholar
  23. 23.
    Fantini J, Yahi N. Brain lipids in synaptic function and neurological disease. In: Clues to innovative therapeutic strategies for brain disorders. San Francisco, CA: Elsevier; 2015.Google Scholar
  24. 24.
    Fantini J, Barrantes FJ. How membrane lipids control the 3D structure and function of receptors. AIMS Biophysics. 2018;5:22–35.CrossRefGoogle Scholar
  25. 25.
    Pydi SP, Jafurulla M, Wai L, Bhullar RP, Chelikani P, Chattopadhyay A. Cholesterol modulates bitter taste receptor function. Biochim Biophys Acta. 2016;1858:2081–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Sharpe LJ, Rao G, Jones PM, Glancey E, Aleidi SM, George AM, Brown AJ, Gelissen IC. Cholesterol sensing by the ABCG1 lipid transporter: requirement of a CRAC motif in the final transmembrane domain. Biochim Biophys Acta. 2015;1851:956–64.CrossRefPubMedGoogle Scholar
  27. 27.
    Robinson LE, Shridar M, Smith P, Murrell-Lagnado RD. Plasma membrane cholesterol as a regulator of human and rodent P2X7 receptor activation and sensitization. J Biol Chem. 2014;289:31983–94.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Singh AK, McMillan J, Bukiya AN, Burton B, Parrill AL, Dopico AM. Multiple cholesterol recognition/interaction amino acid consensus (CRAC) motifs in cytosolic C tail of Slo1 subunit determine cholesterol sensitivity of Ca2+- and voltage-gated K+ (BK) channels. J Biol Chem. 2012;287:20509–21.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Jamin N, Neumann JM, Ostuni MA, Vu TK, Yao ZX, Murail S, Robert JC, Giatzakis C, Papadopoulos V, Lacapere JJ. Characterization of the cholesterol recognition amino acid consensus sequence of the peripheral-type benzodiazepine receptor. Mol Endocrinol. 2005;19:588–94.CrossRefPubMedGoogle Scholar
  30. 30.
    Epand RM. Cholesterol and the interaction of proteins with membrane domains. Prog Lipid Res. 2006;45:279–94.CrossRefPubMedGoogle Scholar
  31. 31.
    Epand RF, Thomas A, Brasseur R, Vishwanathan SA, Hunter E, Epand RM. Juxtamembrane protein segments that contribute to recruitment of cholesterol into domains. Biochemistry. 2006;45:6105–14.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Ulmschneider MB, Sansom MS. Amino acid distributions in integral membrane protein structures. Biochim Biophys Acta. 2001;1512:1–14.CrossRefPubMedGoogle Scholar
  33. 33.
    Ferraro M, Masetti M, Recanatini M, Cavalli A, Bottegoni G. Mapping cholesterol interaction sites on serotonin transporter through coarse-grained molecular dynamics. PLoS One. 2016;11:e0166196.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Morrill GA, Kostellow AB, Gupta RK. The role of receptor topology in the vitamin D3 uptake and Ca(2+) response systems. Biochem Biophys Res Commun. 2016;477:834–40.CrossRefPubMedGoogle Scholar
  35. 35.
    Morrill GA, Kostellow AB, Gupta RK. Computational analysis of the extracellular domain of the Ca(2)(+)-sensing receptor: an alternate model for the Ca(2)(+) sensing region. Biochem Biophys Res Commun. 2015;459:36–41.CrossRefPubMedGoogle Scholar
  36. 36.
    Marsh D, Barrantes FJ. Immobilized lipid in acetylcholine receptor-rich membranes from Torpedo marmorata. Proc Natl Acad Sci U S A. 1978;75:4329–33.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Barrantes FJ. Structural basis for lipid modulation of nicotinic acetylcholine receptor function. Brain Res Brain Res Rev. 2004;47:71–95.CrossRefPubMedGoogle Scholar
  38. 38.
    Song Y, Kenworthy AK, Sanders CR. Cholesterol as a co-solvent and a ligand for membrane proteins. Protein Sci. 2014;23:1–22.CrossRefPubMedGoogle Scholar
  39. 39.
    Goldstein JL, DeBose-Boyd RA, Brown MS. Protein sensors for membrane sterols. Cell. 2006;124:35–46.CrossRefPubMedGoogle Scholar
  40. 40.
    Kuwabara PE, Labouesse M. The sterol-sensing domain: multiple families, a unique role? Trends Genet. 2002;18:193–201.CrossRefPubMedGoogle Scholar
  41. 41.
    Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature. 1990;343:425–30.CrossRefGoogle Scholar
  42. 42.
    Carette JE, Raaben M, Wong AC, Herbert AS, Obernosterer G, Mulherkar N, Kuehne AI, Kranzusch PJ, Griffin AM, Ruthel G, et al. Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. Nature. 2011;477:340–3.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Cote M, Misasi J, Ren T, Bruchez A, Lee K, Filone CM, Hensley L, Li Q, Ory D, Chandran K, Cunningham J. Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection. Nature. 2011;477:344–8.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Gay A, Rye D, Radhakrishnan A. Switch-like responses of two cholesterol sensors do not require protein oligomerization in membranes. Biophys J. 2015;108:1459–69.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Motamed M, Zhang Y, Wang ML, Seemann J, Kwon HJ, Goldstein JL, Brown MS. Identification of luminal loop 1 of Scap protein as the sterol sensor that maintains cholesterol homeostasis. J Biol Chem. 2011;286:18002–12.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Gao Y, Zhou Y, Goldstein JL, Brown MS, Radhakrishnan A. Cholesterol-induced conformational changes in the sterol-sensing domain of the Scap protein suggest feedback mechanism to control cholesterol synthesis. J Biol Chem. 2017;292:8729–37.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Adams CM, Reitz J, De Brabander JK, Feramisco JD, Li L, Brown MS, Goldstein JL. Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanisms, both involving SCAP and Insigs. J Biol Chem. 2004;279:52772–80.CrossRefPubMedGoogle Scholar
  48. 48.
    Infante RE, Abi-Mosleh L, Radhakrishnan A, Dale JD, Brown MS, Goldstein JL. Purified NPC1 protein. I. Binding of cholesterol and oxysterols to a 1278-amino acid membrane protein. J Biol Chem. 2008;283:1052–63.CrossRefPubMedGoogle Scholar
  49. 49.
    Infante RE, Radhakrishnan A, Abi-Mosleh L, Kinch LN, Wang ML, Grishin NV, Goldstein JL, Brown MS. Purified NPC1 protein: II. Localization of sterol binding to a 240-amino acid soluble luminal loop. J Biol Chem. 2008;283:1064–75.CrossRefPubMedGoogle Scholar
  50. 50.
    Li X, Lu F, Trinh MN, Schmiege P, Seemann J, Wang J, Blobel G. 3.3 A structure of Niemann-Pick C1 protein reveals insights into the function of the C-terminal luminal domain in cholesterol transport. Proc Natl Acad Sci U S A. 2017;114:9116–21.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Li X, Wang J, Coutavas E, Shi H, Hao Q, Blobel G. Structure of human Niemann-Pick C1 protein. Proc Natl Acad Sci U S A. 2016;113:8212–7.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Kwon HJ, Abi-Mosleh L, Wang ML, Deisenhofer J, Goldstein JL, Brown MS, Infante RE. Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol. Cell. 2009;137:1213–24.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Gong X, Qian H, Zhou X, Wu J, Wan T, Cao P, Huang W, Zhao X, Wang X, Wang P, et al. Structural insights into the Niemann-Pick C1 (NPC1)-mediated cholesterol transfer and Ebola infection. Cell. 2016;165:1467–78.CrossRefPubMedGoogle Scholar
  54. 54.
    Sever N, Song BL, Yabe D, Goldstein JL, Brown MS, DeBose-Boyd RA. Insig-dependent ubiquitination and degradation of mammalian 3-hydroxy-3-methylglutaryl-CoA reductase stimulated by sterols and geranylgeraniol. J Biol Chem. 2003;278:52479–90.CrossRefPubMedGoogle Scholar
  55. 55.
    Chua NK, Howe V, Jatana N, Thukral L, Brown AJ. A conserved degron containing an amphipathic helix regulates the cholesterol-mediated turnover of human squalene monooxygenase, a rate-limiting enzyme in cholesterol synthesis. J Biol Chem. 2017;292:19959–73.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Albert AD, Young JE, Yeagle PL. Rhodopsin-cholesterol interactions in bovine rod outer segment disk membranes. Biochim Biophys Acta. 1996;1285:47–55.CrossRefPubMedGoogle Scholar
  57. 57.
    Gimpl G, Burger K, Fahrenholz F. Cholesterol as modulator of receptor function. Biochemistry. 1997;36:10959–74.CrossRefPubMedGoogle Scholar
  58. 58.
    Pucadyil TJ, Shrivastava S, Chattopadhyay A. Membrane cholesterol oxidation inhibits ligand binding function of hippocampal serotonin(1A) receptors. Biochem Biophys Res Commun. 2005;331:422–7.CrossRefPubMedGoogle Scholar
  59. 59.
    Caffrey M. A comprehensive review of the lipid cubic phase or in meso method for crystallizing membrane and soluble proteins and complexes. Acta Crystallogr F Struct Biol Commun. 2015;71:3–18.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Caffrey M, Li D, Dukkipati A. Membrane protein structure determination using crystallography and lipidic mesophases: recent advances and successes. Biochemistry. 2012;51:6266–88.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Paila YD, Chattopadhyay A. Membrane cholesterol in the function and organization of G-protein coupled receptors. Subcell Biochem. 2010;51:439–66.CrossRefPubMedGoogle Scholar
  62. 62.
    Hua T, Vemuri K, Nikas SP, Laprairie RB, Wu Y, Qu L, Pu M, Korde A, Jiang S, Ho JH, et al. Crystal structures of agonist-bound human cannabinoid receptor CB1. Nature. 2017;547:468–71.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Gimpl G. Interaction of G protein coupled receptors and cholesterol. Chem Phys Lipids. 2016;199:61–73.CrossRefPubMedGoogle Scholar
  64. 64.
    Paila YD, Tiwari S, Chattopadhyay A. Are specific nonannular cholesterol binding sites present in G-protein coupled receptors? Biochim Biophys Acta. 2009;1788:295–302.CrossRefPubMedGoogle Scholar
  65. 65.
    Clarke OB, Gulbis JM. Oligomerization at the membrane: potassium channel structure and function. Adv Exp Med Biol. 2012;747:122–36.CrossRefPubMedGoogle Scholar
  66. 66.
    Levitan I, Fang Y, Rosenhouse-Dantsker A, Romanenko V. Cholesterol and ion channels. Subcell Biochem. 2010;51:509–49.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Rosenhouse-Dantsker A, Noskov S, Logothetis DE, Levitan I. Cholesterol sensitivity of KIR2.1 depends on functional inter-links between the N and C termini. Channels (Austin). 2013;7:303–12.CrossRefGoogle Scholar
  68. 68.
    Barbera N, Ayee MAA, Akpa BS, Levitan I. Differential effects of sterols on ion channels: stereospecific binding vs stereospecific response. Curr Top Membr. 2017;80:25–50.CrossRefPubMedGoogle Scholar
  69. 69.
    Addona GH, Sandermann H Jr, Kloczewiak MA, Husain SS, Miller KW. Where does cholesterol act during activation of the nicotinic acetylcholine receptor? Biochim Biophys Acta. 1998;1370:299–309.CrossRefPubMedGoogle Scholar
  70. 70.
    Bukiya AN, Osborn CV, Kuntamallappanavar G, Toth PT, Baki L, Kowalsky G, Oh MJ, Dopico AM, Levitan I, Rosenhouse-Dantsker A. Cholesterol increases the open probability of cardiac KACh currents. Biochim Biophys Acta. 2015;1848:2406–13.CrossRefPubMedGoogle Scholar
  71. 71.
    Di Scala C, Chahinian H, Yahi N, Garmy N, Fantini J. Interaction of Alzheimer’s beta-amyloid peptides with cholesterol: mechanistic insights into amyloid pore formation. Biochemistry. 2014;53:4489–502.CrossRefPubMedGoogle Scholar
  72. 72.
    Di Scala C, Troadec JD, Lelievre C, Garmy N, Fantini J, Chahinian H. Mechanism of cholesterol-assisted oligomeric channel formation by a short Alzheimer beta-amyloid peptide. J Neurochem. 2014;128:186–95.CrossRefPubMedGoogle Scholar
  73. 73.
    Irvine GB, El-Agnaf OM, Shankar GM, Walsh DM. Protein aggregation in the brain: the molecular basis for Alzheimer’s and Parkinson’s diseases. Mol Med. 2008;14:451–64.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Harrison RS, Sharpe PC, Singh Y, Fairlie DP. Amyloid peptides and proteins in review. Rev Physiol Biochem Pharmacol. 2007;159:1–77.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Esparza TJ, Zhao H, Cirrito JR, Cairns NJ, Bateman RJ, Holtzman DM, Brody DL. Amyloid-beta oligomerization in Alzheimer dementia versus high-pathology controls. Ann Neurol. 2013;73:104–19.CrossRefPubMedGoogle Scholar
  76. 76.
    Quist A, Doudevski I, Lin H, Azimova R, Ng D, Frangione B, Kagan B, Ghiso J, Lal R. Amyloid ion channels: a common structural link for protein-misfolding disease. Proc Natl Acad Sci U S A. 2005;102:10427–32.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Jang H, Connelly L, Arce FT, Ramachandran S, Lal R, Kagan BL, Nussinov R. Alzheimer’s disease: which type of amyloid-preventing drug agents to employ? Phys Chem Chem Phys. 2013;15:8868–77.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Di Scala C, Yahi N, Boutemeur S, Flores A, Rodriguez L, Chahinian H, Fantini J. Common molecular mechanism of amyloid pore formation by Alzheimer’s beta-amyloid peptide and alpha-synuclein. Sci Rep. 2016;6:28781.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Yahi N, Fantini J. Deciphering the glycolipid code of Alzheimer’s and Parkinson’s amyloid proteins allowed the creation of a universal ganglioside-binding peptide. PLoS One. 2014;9:e104751.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Fantini J, Carlus D, Yahi N. The fusogenic tilted peptide (67-78) of alpha-synuclein is a cholesterol binding domain. Biochim Biophys Acta. 2011;1808:2343–51.CrossRefPubMedGoogle Scholar
  81. 81.
    Charloteaux B, Lorin A, Brasseur R, Lins L. The “Tilted Peptide Theory” links membrane insertion properties and fusogenicity of viral fusion peptides. Protein Pept Lett. 2009;16:718–25.CrossRefPubMedGoogle Scholar
  82. 82.
    Kerr ID, Haider AJ, Gelissen IC. The ABCG family of membrane-associated transporters: you don’t have to be big to be mighty. Br J Pharmacol. 2011;164:1767–79.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Vedhachalam C, Duong PT, Nickel M, Nguyen D, Dhanasekaran P, Saito H, Rothblat GH, Lund-Katz S, Phillips MC. Mechanism of ATP-binding cassette transporter A1-mediated cellular lipid efflux to apolipoprotein A-I and formation of high density lipoprotein particles. J Biol Chem. 2007;282:25123–30.CrossRefPubMedGoogle Scholar
  84. 84.
    Neumann J, Rose-Sperling D, Hellmich UA. Diverse relations between ABC transporters and lipids: an overview. Biochim Biophys Acta. 2017;1859:605–18.CrossRefGoogle Scholar
  85. 85.
    Mendez-Acevedo KM, Valdes VJ, Asanov A, Vaca L. A novel family of mammalian transmembrane proteins involved in cholesterol transport. Sci Rep. 2017;7:7450.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Risselada HJ. Membrane fusion stalks and lipid rafts: a love-hate relationship. Biophys J. 2017;112:2475–8.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Enrich C, Rentero C, Hierro A, Grewal T. Role of cholesterol in SNARE-mediated trafficking on intracellular membranes. J Cell Sci. 2015;128:1071–81.CrossRefPubMedGoogle Scholar
  88. 88.
    Wasser CR, Ertunc M, Liu X, Kavalali ET. Cholesterol-dependent balance between evoked and spontaneous synaptic vesicle recycling. J Physiol. 2007;579:413–29.CrossRefPubMedGoogle Scholar
  89. 89.
    Linetti A, Fratangeli A, Taverna E, Valnegri P, Francolini M, Cappello V, Matteoli M, Passafaro M, Rosa P. Cholesterol reduction impairs exocytosis of synaptic vesicles. J Cell Sci. 2010;123:595–605.CrossRefPubMedGoogle Scholar
  90. 90.
    Hao M, Bogan JS. Cholesterol regulates glucose-stimulated insulin secretion through phosphatidylinositol 4,5-bisphosphate. J Biol Chem. 2009;284:29489–98.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Koseoglu S, Love SA, Haynes CL. Cholesterol effects on vesicle pools in chromaffin cells revealed by carbon-fiber microelectrode amperometry. Anal Bioanal Chem. 2011;400:2963–71.CrossRefPubMedGoogle Scholar
  92. 92.
    Zhang J, Xue R, Ong WY, Chen P. Roles of cholesterol in vesicle fusion and motion. Biophys J. 2009;97:1371–80.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Churchward MA, Rogasevskaia T, Brandman DM, Khosravani H, Nava P, Atkinson JK, Coorssen JR. Specific lipids supply critical negative spontaneous curvature—an essential component of native Ca2+-triggered membrane fusion. Biophys J. 2008;94:3976–86.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Churchward MA, Rogasevskaia T, Hofgen J, Bau J, Coorssen JR. Cholesterol facilitates the native mechanism of Ca2+-triggered membrane fusion. J Cell Sci. 2005;118:4833–48.CrossRefPubMedGoogle Scholar
  95. 95.
    Manes S, del Real G, Martinez AC. Pathogens: raft hijackers. Nat Rev Immunol. 2003;3:557–68.CrossRefPubMedGoogle Scholar
  96. 96.
    Yang ST, Kiessling V, Simmons JA, White JM, Tamm LK. HIV gp41-mediated membrane fusion occurs at edges of cholesterol-rich lipid domains. Nat Chem Biol. 2015;11:424–31.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Scheiffele P, Roth MG, Simons K. Interaction of influenza virus haemagglutinin with sphingolipid-cholesterol membrane domains via its transmembrane domain. EMBO J. 1997;16:5501–8.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Freed EO. HIV-1 assembly, release and maturation. Nat Rev Microbiol. 2015;13:484–96.CrossRefPubMedGoogle Scholar
  99. 99.
    Lee J, Nyenhuis DA, Nelson EA, Cafiso DS, White JM, Tamm LK. Structure of the Ebola virus envelope protein MPER/TM domain and its interaction with the fusion loop explains their fusion activity. Proc Natl Acad Sci U S A. 2017;114:E7987–e7996.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Barrett PJ, Song Y, Van Horn WD, Hustedt EJ, Schafer JM, Hadziselimovic A, Beel AJ, Sanders CR. The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol. Science. 2012;336:1168–71.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Klug YA, Rotem E, Schwarzer R, Shai Y. Mapping out the intricate relationship of the HIV envelope protein and the membrane environment. Biochim Biophys Acta. 2017;1859:550–60.CrossRefGoogle Scholar
  102. 102.
    Epand RM, Sayer BG, Epand RF. Peptide-induced formation of cholesterol-rich domains. Biochemistry. 2003;42:14677–89.CrossRefPubMedGoogle Scholar
  103. 103.
    Epand RF, Sayer BG, Epand RM. The tryptophan-rich region of HIV gp41 and the promotion of cholesterol-rich domains. Biochemistry. 2005;44:5525–31.CrossRefPubMedGoogle Scholar
  104. 104.
    Vishwanathan SA, Thomas A, Brasseur R, Epand RF, Hunter E, Epand RM. Large changes in the CRAC segment of gp41 of HIV do not destroy fusion activity if the segment interacts with cholesterol. Biochemistry. 2008;47:11869–76.CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Vishwanathan SA, Thomas A, Brasseur R, Epand RF, Hunter E, Epand RM. Hydrophobic substitutions in the first residue of the CRAC segment of the gp41 protein of HIV. Biochemistry. 2008;47:124–30.CrossRefPubMedGoogle Scholar
  106. 106.
    Greenwood AI, Pan J, Mills TT, Nagle JF, Epand RM, Tristram-Nagle S. CRAC motif peptide of the HIV-1 gp41 protein thins SOPC membranes and interacts with cholesterol. Biochim Biophys Acta. 2008;1778:1120–30.CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Carravilla P, Cruz A, Martin-Ugarte I, Oar-Arteta IR, Torralba J, Apellaniz B, Perez-Gil J, Requejo-Isidro J, Huarte N, Nieva JL. Effects of HIV-1 gp41-derived virucidal peptides on virus-like lipid membranes. Biophys J. 2017;113:1301–10.CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Chen SS, Yang P, Ke PY, Li HF, Chan WE, Chang DK, Chuang CK, Tsai Y, Huang SC. Identification of the LWYIK motif located in the human immunodeficiency virus type 1 transmembrane gp41 protein as a distinct determinant for viral infection. J Virol. 2009;83:870–83.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Jacques Fantini
    • 1
    • 2
  • Richard M. Epand
    • 3
  • Francisco J. Barrantes
    • 4
  1. 1.INSERM UMR_S 1072MarseilleFrance
  2. 2.Aix-Marseille UniversitéMarseilleFrance
  3. 3.Department of Biochemistry and Biomedical SciencesMcMaster University, Health Sciences CentreHamiltonCanada
  4. 4.Laboratory of Molecular NeurobiologyBiomedical Research Institute (BIOMED), UCA–CONICETBuenos AiresArgentina

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