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'''Unreleased structure'''


The entry 5u74 is ON HOLD  until Paper Publication
==Structure of human Niemann-Pick C1 protein==
<StructureSection load='5u74' size='340' side='right'caption='[[5u74]], [[Resolution|resolution]] 3.33&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5u74]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5U74 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5U74 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.335&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5u74 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u74 OCA], [https://pdbe.org/5u74 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5u74 RCSB], [https://www.ebi.ac.uk/pdbsum/5u74 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5u74 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/NPC1_HUMAN NPC1_HUMAN] Defects in NPC1 are the cause of Niemann-Pick disease type C1 (NPC1) [MIM:[https://omim.org/entry/257220 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.<ref>PMID:9211849</ref> <ref>PMID:11754101</ref> <ref>PMID:9634529</ref> <ref>PMID:10521290</ref> <ref>PMID:10521297</ref> <ref>PMID:10480349</ref> <ref>PMID:11182931</ref> <ref>PMID:11349231</ref> <ref>PMID:11333381</ref> <ref>PMID:11545687</ref> <ref>PMID:11479732</ref> <ref>PMID:12408188</ref> <ref>PMID:12401890</ref> <ref>PMID:12554680</ref> <ref>PMID:12955717</ref> <ref>PMID:16098014</ref> <ref>PMID:15774455</ref> <ref>PMID:16126423</ref> <ref>PMID:16802107</ref>
== Function ==
[https://www.uniprot.org/uniprot/NPC1_HUMAN 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.<ref>PMID:18772377</ref>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Niemann-Pick C1 (NPC1) and NPC2 proteins are indispensable for the export of LDL-derived cholesterol from late endosomes. Mutations in these proteins result in Niemann-Pick type C disease, a lysosomal storage disease. Despite recent reports of the NPC1 structure depicting its overall architecture, the function of its C-terminal luminal domain (CTD) remains poorly understood even though 45% of NPC disease-causing mutations are in this domain. Here, we report a crystal structure at 3.3 A resolution of NPC1* (residues 314-1,278), which-in contrast to previous lower resolution structures-features the entire CTD well resolved. Notably, all eight cysteines of the CTD form four disulfide bonds, one of which (C909-C914) enforces a specific loop that in turn mediates an interaction with a loop of the N-terminal domain (NTD). Importantly, this loop and its interaction with the NTD were not observed in any previous structures due to the lower resolution. Our mutagenesis experiments highlight the physiological relevance of the CTD-NTD interaction, which might function to keep the NTD in the proper orientation for receiving cholesterol from NPC2. Additionally, this structure allows us to more precisely map all of the disease-causing mutations, allowing future molecular insights into the pathogenesis of NPC disease.


Authors: Li, X.
3.3 A structure of Niemann-Pick C1 protein reveals insights into the function of the C-terminal luminal domain in cholesterol transport.,Li X, Lu F, Trinh MN, Schmiege P, Seemann J, Wang J, Blobel G Proc Natl Acad Sci U S A. 2017 Aug 22;114(34):9116-9121. doi:, 10.1073/pnas.1711716114. Epub 2017 Aug 7. PMID:28784760<ref>PMID:28784760</ref>


Description: cdc2
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
[[Category: Li, X]]
<div class="pdbe-citations 5u74" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Li X]]

Latest revision as of 16:22, 4 October 2023

Structure of human Niemann-Pick C1 proteinStructure of human Niemann-Pick C1 protein

Structural highlights

5u74 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.335Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

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]

Publication Abstract from PubMed

Niemann-Pick C1 (NPC1) and NPC2 proteins are indispensable for the export of LDL-derived cholesterol from late endosomes. Mutations in these proteins result in Niemann-Pick type C disease, a lysosomal storage disease. Despite recent reports of the NPC1 structure depicting its overall architecture, the function of its C-terminal luminal domain (CTD) remains poorly understood even though 45% of NPC disease-causing mutations are in this domain. Here, we report a crystal structure at 3.3 A resolution of NPC1* (residues 314-1,278), which-in contrast to previous lower resolution structures-features the entire CTD well resolved. Notably, all eight cysteines of the CTD form four disulfide bonds, one of which (C909-C914) enforces a specific loop that in turn mediates an interaction with a loop of the N-terminal domain (NTD). Importantly, this loop and its interaction with the NTD were not observed in any previous structures due to the lower resolution. Our mutagenesis experiments highlight the physiological relevance of the CTD-NTD interaction, which might function to keep the NTD in the proper orientation for receiving cholesterol from NPC2. Additionally, this structure allows us to more precisely map all of the disease-causing mutations, allowing future molecular insights into the pathogenesis of NPC disease.

3.3 A structure of Niemann-Pick C1 protein reveals insights into the function of the C-terminal luminal domain in cholesterol transport.,Li X, Lu F, Trinh MN, Schmiege P, Seemann J, Wang J, Blobel G Proc Natl Acad Sci U S A. 2017 Aug 22;114(34):9116-9121. doi:, 10.1073/pnas.1711716114. Epub 2017 Aug 7. PMID:28784760[21]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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. ↑ 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 Aug 22;114(34):9116-9121. doi:, 10.1073/pnas.1711716114. Epub 2017 Aug 7. PMID:28784760 doi:http://dx.doi.org/10.1073/pnas.1711716114

5u74, resolution 3.33Å

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