Insights into the Molecular Mechanisms of Cholesterol Binding to the NPC1 and NPC2 Proteins

  • Stephanie M. ColognaEmail author
  • Avia Rosenhouse-DantskerEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1135)


In recent years, a growing number of studies have implicated the coordinated action of NPC1 and NPC2 in intralysosomal transport and efflux of cholesterol. Our current understanding of this process developed with just over two decades of research. Since the cloning of the genes encoding the NPC1 and NPC2 proteins, studies of the biochemical defects observed when either gene is mutated along with computational and structural studies have unraveled key steps in the underlying mechanism. Here, we summarize the major contributions to our understanding of the proposed cholesterol transport controlled by NPC1 and NPC2, and briefly discuss recent findings of cholesterol binding and transport proteins beyond NPC1 and NPC2. We conclude with key questions and major challenges for future research on cholesterol transport by the NPC1 and NPC2 proteins.


Sterol-sensing domain Transport Binding Structure Lysosome Niemann-Pick Disease Type C 





C-terminal domain


Middle luminal domain


Niemann-Pick Type C


N-terminal domain


Sterol sensing domain


  1. 1.
    Yeagle PL. Cholesterol and the cell membrane. Biochim Biophys Acta. 1985;822:267–87.CrossRefPubMedGoogle Scholar
  2. 2.
    Yeagle PL. Modulation of membrane function by cholesterol. Biochimie. 1991;73:1303–10.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Gimpl G, Burger K, Fahrenholz F. Cholesterol as modulator of receptor function. Biochemistry. 1997;36:10959–74.CrossRefPubMedGoogle Scholar
  4. 4.
    Goluszko P, Nowicki B. Membrane cholesterol: a crucial molecule affecting interactions of microbial pathogens with mammalian cells. Infect Immun. 2005;73:7791–6.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ramprasad OG, Srinivas G, Rao KS, Joshi P, Thiery JP, Dufour S, Pande G. Changes in cholesterol levels in the plasma membrane modulate cell signaling and regulate cell adhesion and migration on fibronectin. Cell Motil Cytoskeleton. 2007;64:199–216.CrossRefPubMedGoogle Scholar
  6. 6.
    Rosenhouse-Dantsker A, Mehta D, Levitan I. Regulation of Ion channels by membrane lipids. Compr Physiol. 2012;2:31–68.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Maxfield FR, van Meer G. Cholesterol, the central lipid of mammalian cells. Curr Opin Cell Biol. 2010;22:422–9.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Berg JM, Tymczko JL, Stryer L. Section 26.3. The complex regulation of cholesterol biosynthesis takes place at several levels. In: Berg JM, et al., editors. Biochemistry. 7th ed. New York: W.H. Freeman; 2012. p. 770–9.Google Scholar
  9. 9.
    Afonso SM, Machado RM, Lavrador MS, Quintao ECR, Moore KJ, Lottenberg AM. Molecular pathways underlying cholesterol homeostasis. Nutrients. 2018;10:E760.CrossRefPubMedGoogle Scholar
  10. 10.
    Zhang J, Liu Q. Cholesterol metabolism and homeostasis in the brain. Protein Cell. 2015;6:254–64.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Goedeke L, Fernandez-Hernando C. Regulation of cholesterol homeostasis. Cell Mol Life Sci. 2012;69:915–30.CrossRefPubMedGoogle Scholar
  12. 12.
    Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986;232:34–47.CrossRefPubMedGoogle Scholar
  13. 13.
    Goldstein JL, Dana SE, Faust JR, Beaudet AL, Brown MS. Role of lysosomal acid lipase in the metabolism of plasma low density lipoprotein. Observations in cultured fibroblasts from a patient with cholesteryl ester storage disease. J Biol Chem. 1975;250:8487–95.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Rosenbaum AI, Maxfield FR. Niemann-Pick type C disease: molecular mechanisms and potential therapeutic approaches. J Neurochem. 2011;116:789–95.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Niemann A. Ein unbekanntes Krankheitsbild. Jahrbuch für Kinderheilkunde, vol. 79. Berlin: Neue Folge; 1914. p. 1–10.Google Scholar
  16. 16.
    Pick L. Der Morbus Gaucher und die ihm ähnlichen Krankheiten (die lipoidzellige Splenohepatomegalie Typus Niemann und die diabetische Lipoidzellenhypoplasie der Milz), vol. 29. Berlin: Ergebnisse der Inneren Medizin und Kinderheilkunde; 1926. p. 519–627.Google Scholar
  17. 17.
    Pentchev PG, Comly ME, Kruth HS, Vanier MT, Wenger DA, Patel S, et al. A defect in cholesterol esterification in Niemann-Pick disease (type C) patients. Proc Natl Acad Sci U S A. 1985;82(23):8247–51.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Pentchev PG, Comly ME, Kruth HS, Patel S, Proestel M, Weintroub H. The cholesterol storage disorder of the mutant BALB/c mouse. A primary genetic lesion closely linked to defective esterification of exogenously derived cholesterol and its relationship to human type C Niemann-Pick disease. J Biol Chem. 1986;261(6):2772–7.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Pentchev PG, Kruth HS, Comly ME, Butler JD, Vanier MT, Wenger DA, Patel S. Type C Niemann-Pick disease. A parallel loss of regulatory responses in both the uptake and esterification of low density lipoprotein-derived cholesterol in cultured fibroblasts. J Biol Chem. 1986;261(35):16775–80.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Vanier MT, Rodriguez-Lafrasse C, Rousson R, Gazzah N, Juge MC, Pentchev PG, Revol A, Louisot P, Type C. Niemann-Pick disease: spectrum of phenotypic variation in disruption of intracellular LDL-derived cholesterol processing. Biochim Biophys Acta. 1991;1096:328–37.CrossRefPubMedGoogle Scholar
  21. 21.
    Vanier MT, Wenger DA, Comly ME, Rousson R, Brady RO, Pentchev PG. Niemann-Pick disease group C: clinical variability and diagnosis based on defective cholesterol esterification. A collaborative study on 70 patients. Clin Genet. 1998;33:331–48.CrossRefGoogle Scholar
  22. 22.
    Fink JK, Filling-Katz MR, Sokol J, Cogan DG, Pikus A, Sonies B, Soong B, Pentchev PG, Comly ME, Brady RO. Clinical spectrum of Niemann-Pick disease type C. Neurology. 1989;39:1040–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Schiffmann R. Niemann-Pick disease type C. From bench to bedside. JAMA. 1996;276:561–4.CrossRefPubMedGoogle Scholar
  24. 24.
    Vanier MT, Rodriguez-Lafrasse C, Rousson R, Duthel S, Harzer K, Pentchev PG, Revol A, Louisot P. Type C Niemann-Pick disease: biochemical aspects and phenotypic heterogeneity. Dev Neurosci. 1991;13:307–14.CrossRefPubMedGoogle Scholar
  25. 25.
    Carstea ED, Polymeropoulos MH, Parker CC, Detera-Wadleigh SD, O’Neill RR, Patterson MC, Goldin E, Xiao H, Straub RE, Vanier MT. Linkage of Niemann-Pick disease type C to human chromosome 18. Proc Natl Acad Sci U S A. 1993;90:2002–4.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Vanier MT, Duthel S, Rodriguez-Lafrasse C, Pentchev P, Carstea ED. Genetic heterogeneity in Niemann–Pick C disease: a study using somatic cell hybridization and linkage analysis. Am J Hum Genet. 1996;58:118–25.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Carstea ED, Morris JA, Coleman KG, Loftus SK, Zhang D, Cummings C, et al. Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science. 1997;277(5323):228–31.CrossRefPubMedGoogle Scholar
  28. 28.
    Naureckiene S, Sleat DE, Lackland H, Fensom A, Vanier MT, Wattiaux R, et al. Identification of HE1 as the second gene of Niemann-Pick C disease. Science. 2000;290(5500):2298–301.CrossRefPubMedGoogle Scholar
  29. 29.
    Davidson CD, Steven UW. Niemann-Pick Type C disease—pathophysiology and future perspectives for treatment. US Neurology. 2010;6:88–94.CrossRefGoogle Scholar
  30. 30.
    Crocker AC. The cerebral defect in Tay-Sachs disease and Niemann-Pick disease. J Neurochem. 1961;7:69–80.CrossRefPubMedGoogle Scholar
  31. 31.
    Jones I, He X, Katouzian F, Darroch PI, Schuchman EH. Characterization of common SMPD1 mutations causing types A and B Niemann-Pick disease and generation of mutation-specific mouse models. Mol Genet Metab. 2008;95(3):152–62.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Vanier MT. Complex lipid trafficking in Niemann-Pick disease type C. J Inherit Metab Dis. 2015;38(1):187–99.CrossRefPubMedGoogle Scholar
  33. 33.
    Pentchev PG. Niemann-Pick C research from mouse to gene. Biochim Biophys Acta. 2004;1685(1-3):3–7.CrossRefPubMedGoogle Scholar
  34. 34.
    Patterson MC, Walkley SU. Niemann-Pick disease, type C and Roscoe Brady. Mol Genet Metab. 2017;120(1-2):34–7.CrossRefPubMedGoogle Scholar
  35. 35.
    Adachi M, Volk BW, Schneck L. Animal model of human disease: Niemann-Pick Disease type C. Am J Pathol. 1976;85(1):229–32.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Kruth HS, Comly ME, Butler JD, Vanier MT, Fink JK, Wenger DA, et al. Type C Niemann-Pick disease. Abnormal metabolism of low density lipoprotein in homozygous and heterozygous fibroblasts. J Biol Chem. 1986;261(35):16769–74.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Liscum L, Faust JR. Low density lipoprotein (LDL)-mediated suppression of cholesterol synthesis and LDL uptake is defective in Niemann-Pick type C fibroblasts. J Biol Chem. 1987;262(35):17002–8.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Elleder M, Jirasek A, Smid F, Ledvinova J, Besley GT. Niemann-Pick disease type C. Study on the nature of the cerebral storage process. Acta Neuropathol. 1985;66(4):325–36.CrossRefPubMedGoogle Scholar
  39. 39.
    Kidder LH, Colarusso P, Stewart SA, Levin IW, Appel NM, Lester DS, et al. Infrared spectroscopic imaging of the biochemical modifications induced in the cerebellum of the Niemann-Pick type C mouse. J Biomed Opt. 1999;4(1):7–13.CrossRefPubMedGoogle Scholar
  40. 40.
    German DC, Quintero EM, Liang CL, Ng B, Punia S, Xie C, et al. Selective neurodegeneration, without neurofibrillary tangles, in a mouse model of Niemann-Pick C disease. J Comp Neurol. 2001;433(3):415–25.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Tanaka J, Nakamura H, Miyawaki S. Cerebellar involvement in murine sphingomyelinosis: a new model of Niemann-Pick disease. J Neuropathol Exp Neurol. 1988;47(3):291–300.CrossRefPubMedGoogle Scholar
  42. 42.
    Higashi Y, Murayama S, Pentchev PG, Suzuki K. Cerebellar degeneration in the Niemann-Pick type C mouse. Acta Neuropathol. 1993;85(2):175–84.CrossRefPubMedGoogle Scholar
  43. 43.
    Sarna JR, Larouche M, Marzban H, Sillitoe RV, Rancourt DE, Hawkes R. Patterned Purkinje cell degeneration in mouse models of Niemann-Pick type C disease. J Comp Neurol. 2003;456(3):279–91.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Fu R, Yanjanin NM, Bianconi S, Pavan WJ, Porter FD. Oxidative stress in Niemann-Pick disease, type C. Mol Genet Metab. 2010;101(2-3):214–8.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Klein A, Maldonado C, Vargas LM, Gonzalez M, Robledo F, Perez de Arce K, et al. Oxidative stress activates the c-Abl/p73 proapoptotic pathway in Niemann-Pick type C neurons. Neurobiol Dis. 2011;41(1):209–18.CrossRefPubMedGoogle Scholar
  46. 46.
    Lloyd-Evans E, Morgan AJ, He X, Smith DA, Elliot-Smith E, Sillence DJ, et al. Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nat Med. 2008;14(11):1247–55.CrossRefPubMedGoogle Scholar
  47. 47.
    Saez PJ, Orellana JA, Vega-Riveros N, Figueroa VA, Hernandez DE, Castro JF, et al. Disruption in connexin-based communication is associated with intracellular Ca(2)(+) signal alterations in astrocytes from Niemann-Pick type C mice. PLoS One. 2013;8(8):e71361.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Byun K, Kim D, Bayarsaikhan E, Oh J, Kim J, Kwak G, et al. Changes of calcium binding proteins, c-Fos and COX in hippocampal formation and cerebellum of Niemann-Pick, type C mouse. J Chem Neuroanat. 2013;52:1–8.CrossRefPubMedGoogle Scholar
  49. 49.
    Kennedy BE, LeBlanc VG, Mailman TM, Fice D, Burton I, Karakach TK, et al. Pre-symptomatic activation of antioxidant responses and alterations in glucose and pyruvate metabolism in Niemann-Pick Type C1-deficient murine brain. PLoS One. 2013;8(12):e82685.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Elrick MJ, Lieberman AP. Autophagic dysfunction in a lysosomal storage disorder due to impaired proteolysis. Autophagy. 2013;9(2):234–5.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Cougnoux A, Cluzeau C, Mitra S, Li R, Williams I, Burkert K, et al. Necroptosis in Niemann-Pick disease, type C1: a potential therapeutic target. Cell Death Dis. 2016;7:e2147.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Cologna SM, Cluzeau CV, Yanjanin NM, Blank PS, Dail MK, Siebel S, et al. Human and mouse neuroinflammation markers in Niemann-Pick disease, type C1. J Inherit Metab Dis. 2014;37(1):83–92.CrossRefPubMedGoogle Scholar
  53. 53.
    Zervas M, Dobrenis K, Walkley SU. Neurons in Niemann-Pick disease type C accumulate gangliosides as well as unesterified cholesterol and undergo dendritic and axonal alterations. J Neuropathol Exp Neurol. 2001;60(1):49–64.CrossRefPubMedGoogle Scholar
  54. 54.
    German DC, Quintero EM, Liang C, Xie C, Dietschy JM. Degeneration of neurons and glia in the Niemann-Pick C mouse is unrelated to the low-density lipoprotein receptor. Neuroscience. 2001;105(4):999–1005.CrossRefPubMedGoogle Scholar
  55. 55.
    Walkley SU, Suzuki K. Consequences of NPC1 and NPC2 loss of function in mammalian neurons. Biochim Biophys Acta. 2004;1685(1-3):48–62.CrossRefPubMedGoogle Scholar
  56. 56.
    Kirchhoff C, Osterhoff C, Young L. Molecular cloning and characterization of HE1, a major secretory protein of the human epididymis. Biol Reprod. 1996;54(4):847–56.CrossRefPubMedGoogle Scholar
  57. 57.
    Okamura N, Kiuchi S, Tamba M, Kashima T, Hiramoto S, Baba T, Dacheux F, Dacheux JL, Sugita Y, Jin YZ. A porcine homolog of the major secretory protein of human epididymis, HE1, specifically binds cholesterol. Biochim Biophys Acta. 1999;1438:377–87.CrossRefPubMedGoogle Scholar
  58. 58.
    Friedland N, Liou HL, Lobel P, Stock AM. Structure of a cholesterol-binding protein deficient in Niemann–Pick type C2 disease. Proc Natl Acad Sci U S A. 2003;100:2512–7.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Ko DC, Binkley J, Sidow A, Scott MP. The integrity of a cholesterol-binding pocket in Niemann-Pick C2 protein is necessary to control lysosome cholesterol levels. Proc Natl Acad Sci U S A. 2003;100:2518–25.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Sleat DE, Wiseman JA, El-Banna M, Price SM, Verot L, Shen MM, Tint GS, Vanier MT, Walkley SU, Lobel P. Genetic evidence for nonredundant functional cooperativity between NPC1 and NPC2 in lipid transport. Proc Natl Acad Sci U S A. 2004;101:5886–91.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Cheruku SR, Xu Z, Dutia R, Lobel P, Storch J. Mechanism of cholesterol transfer from the Niemann-Pick type C2 protein to model membranes supports a role in lysosomal cholesterol transport. J Biol Chem. 2006;281:31594–604.CrossRefPubMedGoogle Scholar
  62. 62.
    McCauliff LA, Xu Z, Li R, Kodukula S, Ko DC, Scott MP, Kahn PC, Storch J. Multiple surface regions on the Niemann-Pick C2 protein facilitate intracellular cholesterol transport. J Biol Chem. 2015;290:27321–31.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Xu S, Benoff B, Liou HL, Lobel P, Stock AM. Structural basis of sterol binding by NPC2, a lysosomal protein deficient in Niemann–Pick type C2 disease. J Biol Chem. 2007;282:23525–31.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Loftus SK, Morris JA, Carstea ED, Gu JZ, Cummings C, Brown A, et al. Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene. Science. 1997;277(5323):232–5.CrossRefPubMedGoogle Scholar
  65. 65.
    Patterson MC, Vanier MT, Suzuki K, Morris JA, Carstea E, Neufeld EB, Blanchette-Mackie JE, Pentchev PG. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease, vol. III. New York: McGraw-Hill; 2001. p. 3611–33.Google Scholar
  66. 66.
    Watari H, Blanchette-Mackie EJ, Dwyer NK, Watari M, Neufeld EB, Patel S, Pentchev PG, Strauss JF III. Mutations in the leucine zipper motif and sterol-sensing domain inactivate the Niemann-Pick C1 glycoprotein. J Biol Chem. 1999;274:21861–6.CrossRefPubMedGoogle Scholar
  67. 67.
    Ohgami N, Ko DC, Thomas M, Scott MP, Chang CC, Chang TY. Binding between the Niemann-Pick C1 protein and a photoactivatable cholesterol analog requires a functional sterol-sensing domain. Proc Natl Acad Sci U S A. 2004;101(34):12473–8.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Ioannou YA. Multidrug permeases and subcellular cholesterol transport. Nat Rev Mol Cell Biol. 2001;2:657–68.CrossRefPubMedGoogle Scholar
  69. 69.
    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
  70. 70.
    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
  71. 71.
    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
  72. 72.
    Ohgane K, Karaki F, Dodo K, Hashimoto Y. Discovery of oxysterol-derived pharmacological chaperones for NPC1: implication for the existence of second sterol-binding site. Chem Biol. 2013;20:391–402.CrossRefPubMedGoogle Scholar
  73. 73.
    Gong X, Qian H, Zhou X, Wu J, Wan T, Cao P, Huang W, Zhao X, Wang X, Wang P, Shi Y, Gao GF, Zhou Q, Yan N. Structural insights into the Niemann-Pick C1 (NPC1)-mediated cholesterol transfer and Ebola infection. Cell. 2016;165(6):1467–78.CrossRefPubMedGoogle Scholar
  74. 74.
    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
  75. 75.
    Infante RE, Wang ML, Radhakrishnan A, Kwon HJ, Brown MS, Goldstein JL. NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes. Proc Natl Acad Sci U S A. 2008;105:15287–92.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Wang ML, Motamed M, Infante RE, Abi-Mosleh L, Kwon HJ, Brown MS, Goldstein JL. Identification of surface residues on Niemann-Pick C2 essential for hydrophobic handoff of cholesterol to NPC1 in lysosomes. Cell Metab. 2010;12:166–73.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Deffieu MS, Pfeffer SR. Niemann-Pick type C 1 function requires lumenal domain residues that mediate cholesterol-dependent NPC2 binding. Proc Natl Acad Sci U S A. 2011;108:18932–6.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Estiu G, Khatri N, Wiest O. Computational studies of the cholesterol transport between NPC2 and the N-terminal domain of NPC1 (NPC1(NTD)). Biochemistry. 2013;52(39):6879–91.CrossRefPubMedGoogle Scholar
  79. 79.
    Elghobashi-Meinhardt N. Niemann-Pick type C disease: a QM/MM study of conformational changes in cholesterol in the NPC1(NTD) and NPC2 binding pockets. Biochemistry. 2014;53:6603–14.CrossRefPubMedGoogle Scholar
  80. 80.
    Li X, Saha P, Li J, Blobel G, Pfeffer SR. Clues to the mechanism of cholesterol transfer from the structure of NPC1 middle lumenal domain bound to NPC2. Proc Natl Acad Sci U S A. 2016;113:10079–84.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Li X, Lu F, Trinh MN, Schmiege P, Seemann J, Wang J, Blobel G. 3.3 Å 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(34):9116–21.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Wüstner D, Solanko K. How cholesterol interacts with proteins and lipids during its intracellular transport. Biochim Biophys Acta. 1848;2015:1908–26.Google Scholar
  83. 83.
    Xavier BM, Jennings WJ, Zein AA, Wang J, Lee JY. Structural snapshot of the cholesterol-transport ATP-binding cassette proteins. Biochem Cell Biol. 2018:1–10.Google Scholar
  84. 84.
    Litvinov DY, Savushkin EV, Dergunov AD. Intracellular and plasma membrane events in cholesterol transport and homeostasis. J Lipids. 2018;2018:3965054.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Maxfield FR, Iaea DB, Pipalia NH. Role of STARD4 and NPC1 in intracellular sterol transport. Biochem Cell Biol. 2016;94(6):499–506.CrossRefPubMedGoogle Scholar
  86. 86.
    Soffientini U, Graham A. Intracellular cholesterol transport proteins: roles in health and disease. Clin Sci (Lond). 2016;130(21):1843–59.CrossRefGoogle Scholar
  87. 87.
    Du X, Brown AJ, Yang H. Novel mechanisms of intracellular cholesterol transport: oxysterol-binding proteins and membrane contact sites. Curr Opin Cell Biol. 2015;35:37–42.CrossRefPubMedGoogle Scholar
  88. 88.
    Sandhu J, Li S, Fairall L, Pfisterer SG, Gurnett JE, Xiao X, et al. Aster proteins facilitate nonvesicular plasma membrane to ER cholesterol transport in mammalian cells. Cell. 2018;175(2):514–29.. e20CrossRefPubMedGoogle Scholar
  89. 89.
    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
  90. 90.
    Cooper MK, Wassif CA, Krakowiak PA, Taipale J, Gong R, Kelley RI, Porter FD, Beachy PA. A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis. Nat Genet. 2003;33:508–13.CrossRefPubMedGoogle Scholar
  91. 91.
    Huang P, Nedelcu D, Watanabe M, Jao C, Kim Y, Liu J, Salic A. Cellular cholesterol directly activates smoothened in hedgehog signaling. Cell. 2016;166:1176–1187.e14.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Huang P, Zheng S, Wierbowski BM, Kim Y, Nedelcu D, Aravena L, Liu J, Kruse AC, Salic A. Structural basis of smoothened activation in Hedgehog signaling. Cell. 2018;174:312–324.e6.CrossRefPubMedGoogle Scholar
  93. 93.
    Luchetti G, Sircar R, Kong JH, Nachtergaele S, Sagner A, Byrne EF, Covey DF, Siebold C, Rohatgi R. Cholesterol activates the G-protein coupled receptor smoothened to promote Hedgehog signaling. Elife. 2016;5:e20304.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Myers BR, Neahring L, Zhang Y, Roberts KJ, Beachy PA. Rapid, direct activity assays for Smoothened reveal Hedgehog pathway regulation by membrane cholesterol and extracellular sodium. Proc Natl Acad Sci U S A. 2017;114:E11141–50.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Xiao X, Tang JJ, Peng C, Wang Y, Fu L, Qiu ZP, Xiong Y, Yang LF, Cui HW, He XL, et al. Cholesterol modification of smoothened is required for Hedgehog signaling. Mol Cell. 2017;66:154–162.e10.CrossRefPubMedGoogle Scholar
  96. 96.
    Zhang Y, Bulkley DP, Xin Y, Roberts KJ, Asarnow DE, Sharma A, et al. Structural basis for cholesterol transport-like activity of the Hedgehog receptor patched. Cell. 2018;175(5):1352–64.e14.CrossRefPubMedGoogle Scholar
  97. 97.
    Qi X, Schmiege P, Coutavas E, Wang J, Li X. Structures of human Patched and its complex with native palmitoylated sonic hedgehog. Nature. 2018;560(7716):128–32.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Liu R, Lu P, Chu JW, Sharom FJ. Characterization of fluorescent sterol binding to purified human NPC1. J Biol Chem. 2009;284:1840–52.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of ChemistryUniversity of Illinois at ChicagoChicagoUSA
  2. 2.Laboratory for Integrative NeuroscienceUniversity of Illinois at ChicagoChicagoUSA

Personalised recommendations