6w5v

Structural highlights

Disease

[NPC1_HUMAN] Defects in NPC1 are the cause of Niemann-Pick disease type C1 (NPC1) [MIM:257220]. A lysosomal storage disorder that affects the viscera and the central nervous system. It is due to defective intracellular processing and transport of low-density lipoprotein derived cholesterol. It causes accumulation of cholesterol in lysosomes, with delayed induction of cholesterol homeostatic reactions. Niemann-Pick disease type C1 has a highly variable clinical phenotype. Clinical features include variable hepatosplenomegaly and severe progressive neurological dysfunction such as ataxia, dystonia and dementia. The age of onset can vary from infancy to late adulthood. An allelic variant of Niemann-Pick disease type C1 is found in people with Nova Scotia ancestry. Patients with the Nova Scotian clinical variant are less severely affected.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19]} [NPC2_HUMAN] Niemann-Pick disease type C, severe perinatal form;Niemann-Pick disease type C, juvenile neurologic onset;Niemann-Pick disease type C, severe early infantile neurologic onset;Niemann-Pick disease type C, adult neurologic onset;Niemann-Pick disease type C, late infantile neurologic onset. The disease is caused by mutations affecting the gene represented in this entry.

Function

[NPC1_HUMAN] Intracellular cholesterol transporter which acts in concert with NPC2 and plays an important role in the egress of cholesterol from the endosomal/lysosomal compartment. Both NPC1 and NPC2 function as the cellular 'tag team duo' (TTD) to catalyze the mobilization of cholesterol within the multivesicular environment of the late endosome (LE) to effect egress through the limiting bilayer of the LE. NPC2 binds unesterified cholesterol that has been released from LDLs in the lumen of the late endosomes/lysosomes and transfers it to the cholesterol-binding pocket of the N-terminal domain of NPC1. Cholesterol binds to NPC1 with the hydroxyl group buried in the binding pocket and is exported from the limiting membrane of late endosomes/ lysosomes to the ER and plasma membrane by an unknown mechanism. Binds oxysterol with higher affinity than cholesterol. May play a role in vesicular trafficking in glia, a process that may be crucial for maintaining the structural and functional integrity of nerve terminals.^[20] [NPC2_HUMAN] Intracellular cholesterol transporter which acts in concert with NPC1 and plays an important role in the egress of cholesterol from the endosomal/lysosomal compartment. Both NPC1 and NPC2 function as the cellular 'tag team duo' (TTD) to catalyze the mobilization of cholesterol within the multivesicular environment of the late endosome (LE) to effect egress through the limiting bilayer of the LE. NPC2 binds unesterified cholesterol that has been released from LDLs in the lumen of the late endosomes/lysosomes and transfers it to the cholesterol-binding pocket of the N-terminal domain of NPC1. Cholesterol binds to NPC1 with the hydroxyl group buried in the binding pocket and is exported from the limiting membrane of late endosomes/ lysosomes to the ER and plasma membrane by an unknown mechanism. The secreted form of NCP2 regulates biliary cholesterol secretion via stimulation of ABCG5/ABCG8-mediated cholesterol transport.^{[21] [22] [23]}

References

1. ↑ Carstea ED, Morris JA, Coleman KG, Loftus SK, Zhang D, Cummings C, Gu J, Rosenfeld MA, Pavan WJ, Krizman DB, Nagle J, Polymeropoulos MH, Sturley SL, Ioannou YA, Higgins ME, Comly M, Cooney A, Brown A, Kaneski CR, Blanchette-Mackie EJ, Dwyer NK, Neufeld EB, Chang TY, Liscum L, Strauss JF 3rd, Ohno K, Zeigler M, Carmi R, Sokol J, Markie D, O'Neill RR, van Diggelen OP, Elleder M, Patterson MC, Brady RO, Vanier MT, Pentchev PG, Tagle DA. Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science. 1997 Jul 11;277(5323):228-31. PMID:9211849
2. ↑ Bauer P, Knoblich R, Bauer C, Finckh U, Hufen A, Kropp J, Braun S, Kustermann-Kuhn B, Schmidt D, Harzer K, Rolfs A. NPC1: Complete genomic sequence, mutation analysis, and characterization of haplotypes. Hum Mutat. 2002 Jan;19(1):30-8. PMID:11754101 doi:10.1002/humu.10016
3. ↑ Greer WL, Riddell DC, Gillan TL, Girouard GS, Sparrow SM, Byers DM, Dobson MJ, Neumann PE. The Nova Scotia (type D) form of Niemann-Pick disease is caused by a G3097-->T transversion in NPC1. Am J Hum Genet. 1998 Jul;63(1):52-4. PMID:9634529 doi:10.1086/301931
4. ↑ Greer WL, Dobson MJ, Girouard GS, Byers DM, Riddell DC, Neumann PE. Mutations in NPC1 highlight a conserved NPC1-specific cysteine-rich domain. Am J Hum Genet. 1999 Nov;65(5):1252-60. PMID:10521290
5. ↑ Millat G, Marcais C, Rafi MA, Yamamoto T, Morris JA, Pentchev PG, Ohno K, Wenger DA, Vanier MT. Niemann-Pick C1 disease: the I1061T substitution is a frequent mutant allele in patients of Western European descent and correlates with a classic juvenile phenotype. Am J Hum Genet. 1999 Nov;65(5):1321-9. PMID:10521297 doi:10.1086/302626
6. ↑ Yamamoto T, Nanba E, Ninomiya H, Higaki K, Taniguchi M, Zhang H, Akaboshi S, Watanabe Y, Takeshima T, Inui K, Okada S, Tanaka A, Sakuragawa N, Millat G, Vanier MT, Morris JA, Pentchev PG, Ohno K. NPC1 gene mutations in Japanese patients with Niemann-Pick disease type C. Hum Genet. 1999 Jul-Aug;105(1-2):10-6. PMID:10480349
7. ↑ Yamamoto T, Ninomiya H, Matsumoto M, Ohta Y, Nanba E, Tsutsumi Y, Yamakawa K, Millat G, Vanier MT, Pentchev PG, Ohno K. Genotype-phenotype relationship of Niemann-Pick disease type C: a possible correlation between clinical onset and levels of NPC1 protein in isolated skin fibroblasts. J Med Genet. 2000 Sep;37(9):707-12. PMID:11182931
8. ↑ Sun X, Marks DL, Park WD, Wheatley CL, Puri V, O'Brien JF, Kraft DL, Lundquist PA, Patterson MC, Pagano RE, Snow K. Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1. Am J Hum Genet. 2001 Jun;68(6):1361-72. Epub 2001 May 9. PMID:11349231 doi:S0002-9297(07)61047-7
9. ↑ Millat G, Marcais C, Tomasetto C, Chikh K, Fensom AH, Harzer K, Wenger DA, Ohno K, Vanier MT. Niemann-Pick C1 disease: correlations between NPC1 mutations, levels of NPC1 protein, and phenotypes emphasize the functional significance of the putative sterol-sensing domain and of the cysteine-rich luminal loop. Am J Hum Genet. 2001 Jun;68(6):1373-85. Epub 2001 May 1. PMID:11333381 doi:10.1086/320606
10. ↑ Meiner V, Shpitzen S, Mandel H, Klar A, Ben-Neriah Z, Zlotogora J, Sagi M, Lossos A, Bargal R, Sury V, Carmi R, Leitersdorf E, Zeigler M. Clinical-biochemical correlation in molecularly characterized patients with Niemann-Pick type C. Genet Med. 2001 Sep-Oct;3(5):343-8. PMID:11545687
11. ↑ Ribeiro I, Marcao A, Amaral O, Sa Miranda MC, Vanier MT, Millat G. Niemann-Pick type C disease: NPC1 mutations associated with severe and mild cellular cholesterol trafficking alterations. Hum Genet. 2001 Jul;109(1):24-32. PMID:11479732
12. ↑ Kaminski WE, Klunemann HH, Ibach B, Aslanidis C, Klein HE, Schmitz G. Identification of novel mutations in the NPC1 gene in German patients with Niemann-Pick C disease. J Inherit Metab Dis. 2002 Sep;25(5):385-9. PMID:12408188
13. ↑ Tarugi P, Ballarini G, Bembi B, Battisti C, Palmeri S, Panzani F, Di Leo E, Martini C, Federico A, Calandra S. Niemann-Pick type C disease: mutations of NPC1 gene and evidence of abnormal expression of some mutant alleles in fibroblasts. J Lipid Res. 2002 Nov;43(11):1908-19. PMID:12401890
14. ↑ Blom TS, Linder MD, Snow K, Pihko H, Hess MW, Jokitalo E, Veckman V, Syvanen AC, Ikonen E. Defective endocytic trafficking of NPC1 and NPC2 underlying infantile Niemann-Pick type C disease. Hum Mol Genet. 2003 Feb 1;12(3):257-72. PMID:12554680
15. ↑ Park WD, O'Brien JF, Lundquist PA, Kraft DL, Vockley CW, Karnes PS, Patterson MC, Snow K. Identification of 58 novel mutations in Niemann-Pick disease type C: correlation with biochemical phenotype and importance of PTC1-like domains in NPC1. Hum Mutat. 2003 Oct;22(4):313-25. PMID:12955717 doi:http://dx.doi.org/10.1002/humu.10255
16. ↑ Fernandez-Valero EM, Ballart A, Iturriaga C, Lluch M, Macias J, Vanier MT, Pineda M, Coll MJ. Identification of 25 new mutations in 40 unrelated Spanish Niemann-Pick type C patients: genotype-phenotype correlations. Clin Genet. 2005 Sep;68(3):245-54. PMID:16098014 doi:CGE490
17. ↑ Yang CC, Su YN, Chiou PC, Fietz MJ, Yu CL, Hwu WL, Lee MJ. Six novel NPC1 mutations in Chinese patients with Niemann-Pick disease type C. J Neurol Neurosurg Psychiatry. 2005 Apr;76(4):592-5. PMID:15774455 doi:10.1136/jnnp.2004.046045
18. ↑ Millat G, Bailo N, Molinero S, Rodriguez C, Chikh K, Vanier MT. Niemann-Pick C disease: use of denaturing high performance liquid chromatography for the detection of NPC1 and NPC2 genetic variations and impact on management of patients and families. Mol Genet Metab. 2005 Sep-Oct;86(1-2):220-32. PMID:16126423 doi:10.1016/j.ymgme.2005.07.007
19. ↑ Dvorakova L, Sikora J, Hrebicek M, Hulkova H, Bouckova M, Stolnaja L, Elleder M. Subclinical course of adult visceral Niemann-Pick type C1 disease. A rare or underdiagnosed disorder? J Inherit Metab Dis. 2006 Aug;29(4):591. Epub 2006 Jun 26. PMID:16802107 doi:10.1007/s10545-006-0330-z
20. ↑ 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 Oct 7;105(40):15287-92. doi:, 10.1073/pnas.0807328105. Epub 2008 Sep 4. PMID:18772377 doi:10.1073/pnas.0807328105
21. ↑ Liou HL, Dixit SS, Xu S, Tint GS, Stock AM, Lobel P. NPC2, the protein deficient in Niemann-Pick C2 disease, consists of multiple glycoforms that bind a variety of sterols. J Biol Chem. 2006 Dec 1;281(48):36710-23. Epub 2006 Oct 2. PMID:17018531 doi:http://dx.doi.org/10.1074/jbc.M608743200
22. ↑ 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 Oct 7;105(40):15287-92. doi:, 10.1073/pnas.0807328105. Epub 2008 Sep 4. PMID:18772377 doi:10.1073/pnas.0807328105
23. ↑ Xu Z, Farver W, Kodukula S, Storch J. Regulation of sterol transport between membranes and NPC2. Biochemistry. 2008 Oct 21;47(42):11134-43. doi: 10.1021/bi801328u. Epub 2008 Sep , 30. PMID:18823126 doi:http://dx.doi.org/10.1021/bi801328u
24. ↑ Qian H, Wu X, Du X, Yao X, Zhao X, Lee J, Yang H, Yan N. Structural Basis of Low-pH-Dependent Lysosomal Cholesterol Egress by NPC1 and NPC2. Cell. 2020 Jun 11. pii: S0092-8674(20)30615-2. doi: 10.1016/j.cell.2020.05.020. PMID:32544384 doi:http://dx.doi.org/10.1016/j.cell.2020.05.020