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2.A.6.6.1
Niemann-Pick C1 and C2 disease proteins, NPC1 and NPC2, together may form a lipid/cholesterol exporter from lysosomes to other cellular sites including the plasma membrane (Sleat et al., 2004; Kennedy et al. 2014). NPC1 or NPC2 deficiency causes lysosomal retention of cholesterol, sphingolipids, phospholipids, and glycolipids as well as neuronal dysfunction and neurodegeneration (Infante et al. 2008a). Cholesterol binds to the sterol-sensing domain (Ohgami et al. 2004). Increased mitochondrial cholesterol, observed in NPC1 or NPC2 deficiency, causes oxidative stress and increased rates of glycolysis and lactate release (Kennedy et al. 2014).  NPC1 binds cholesterol, 25-hydroxycholesterol and various oxysterols (Infante et al. 2008b; Liu et al., 2009 ). Soluble NPC2 binds cholesterol, and then passes it to the N-terminal domain of membranous NPC1 (Abi-Mosleh et al., 2009). Cholesterol trafficking in Niemann-Pick C-deficient cells was reviewed by Peake and Vance (2010). NPC1 is a late-endosomal membrane protein involved in trafficking of LDL- derived cholesterol, Niemann-Pick disease type C, and Ebola virus infection.  It is the Ebola virus receptor. It contains 13 TMSs, five of which are thought to represent a "sterol-sensing domain", also present in other key regulatory proteins of cholesterol biosynthesis, uptake, and signaling. A crystal structure of a large fragment of human NPC1 at 3.6 Å resolution revealed internal twofold pseudosymmetry along TMSs 2-13 and two structurally homologous domains that protrude 60 Å into the endosomal lumen (Li et al. 2016). NPC1's sterol sensing domain forms a cavity that is accessible from both the luminal bilayer leaflet and the endosomal lumen; this cavity is large enough to accommodate one cholesterol molecule. A model was proposed for  cholesterol sensing and transport (Li et al. 2016).  Lysosomal cholesterol activates TORC1 via an SLC38A9-Niemann-Pick C1 signaling complex (Castellano et al. 2017).  Gong et al. 2016 presented a 4.4 Å structure of the full-length human NPC1 and a low-resolution reconstruction of NPC1 in complex with the cleaved glycoprotein (GPcl) of EBOV, both determined by single-particle electron cryomicroscopy. NPC1 contains three distinct lumenal domains A (also designated NTD), C, and I. TMSs 2-13 exhibit a typical RND fold, among which TMSs 3-7 constitute the sterol-sensing domain conserved in several proteins involved in cholesterol metabolism and signaling. A trimeric EBOV-GPcl binds to one NPC1 monomer through domain C (Gong et al. 2016). The effects of disease-causing mutations on quality control pathways involving the lysosome and endoplasmic reticulum, and how it functions to clear the most common mutant protein found in Niemann-Pick type C patients have been reviewed (Schultz et al. 2016). In the same review, knowledge concerning the mechanisms that degrade misfolded transmembrane proteins in the endoplasmic reticulum is presented. Cholesterol esters are components of low density lipoprotein (LDL), which is brought into the cells of various tissues by targeted endocytosis. Within the endosomes, cholesterol esters are hydrolyzed, releasing free cholesterol, which is finally exported out of the endosome by NPC1 with assistance from a soluble protein NPC2 (Nikaido 2018). The transmembrane helices in the N-terminal half (the SSD, sterol-sensing domain) of NPC1 are homologous to the sterol-binding domains of HMG-CoA reductase, as well as the regulator of cholesterol-regulated transcription activation, SCAP. The domain that binds cholesterol with the highest affinity, within NPC1, however, is the NTD. In the NPC2-NPC1 complex, the substrate is captured at a location far away from the membrane by NPC2, and then is brought to a location close to the membrane surface (NTD of NPC1), and is finally moved to the intramembranous region of NPC1. Degradation occurs via two pathways, the proteasome following MARCH6-dependent ERAD, and an autophagic pathway called the selective ER autophagy (ER-phagy) (Schultz et al. 2018). NPC1 exports LDL-derived cholesterol from lysosomes by carrying it through the 80 Å glycocalyx and the 40 Å lipid bilayer. Transport begins when cholesterol binds to the N-terminal domain (NTD) of NPC1, which projects to the surface of the glycocalyx. Trinh et al. 2018 reconstituted cholesterol transport by expressing the NTD as a fragment separate from the remaining portion of NPC1. When co-expressed, the two NPC1 fragments reconstitute cholesterol transport and showed that cholesterol can be transferred from the NTD of one full-length NPC1 to another NPC1 molecule that lacks the NTD. The locations of buried amino acids and docking studies have identified putative lipid binding domains that are in close proximity to amino acids that, when mutated, are connected to NPC1 loss-of-function (Elghobashi-Meinhardt 2019). Niemann-Pick type C 1 function requires lumenal domain residues that mediate cholesterol-dependent NPC2 binding, and lysosomal cholesterol egress requires both NPC1 and NPC2. Qian et al. 2020 presented systematic structural characterizations that revealed the molecular basis for low-pH-dependent cholesterol delivery from NPC2 to the transmembrane domain of NPC1. At pH 8.0, similar structures of NPC1 were obtained in nanodiscs and in detergent. A tunnel connecting the N-terminal domain (NTD) and the transmembrane sterol-sensing domain (SSD) was unveiled. At pH 5.5, the NTD exhibits two conformations, suggesting the motion for cholesterol delivery to the tunnel. A cholesterol molecule was found at the membrane boundary of the tunnel, and TMS2 moves toward formation of a surface pocket on the SSD. The structure of the NPC1-NPC2 complex at 4.0 Å resolution was obtained at pH 5.5, elucidating the molecular basis for cholesterol handoff from NPC2 to NPC1(NTD) (Qian et al. 2020). Genetic diversity in Niemann-Pick C1 can be managed through modulation of the Hsp70 chaperone system (Wang et al. 2020). The NPC1 protein is evolutionarily conserved with homologues reported in yeast to humans; NPC2 is present in C. elegans to humans. While neurons in mammalian models of NPC1 and NPC2 diseases exhibit many changes that are similar to those in humans (e.g., endosomal/lysosomal storage, Golgi fragmentation, neuroaxonal dystrophy, neurodegeneration), a reduced degree of ectopic dendritogenesis and an absence of neurofibrillary tangles (NFTs) in these species suggest important differences in the way lower mammalian neurons respond to NPC1/NPC2 loss of function (Walkley and Suzuki 2004). Cholesterol transport studies using wild-type NPC1 and the P691S mutant suggest changes in dynamical behavior as determined using molecular dynamics simulations (Elghobashi-Meinhardt 2020). NPC1 mutations cause variable disease phenotypes (Musalkova et al. 2020). Filoviruses, including marburgviruses and ebolaviruses, have a single transmembrane glycoprotein (GP) that facilitates their entry into cells. During entry, GP needs to be cleaved by host proteases to expose the receptor-binding site that binds to the endosomal receptor Niemann-Pick C1 (NPC1) protein. Crystal structural analyses of the cleaved GP (GPcl) of Ebola virus (EBOV) in complex with human NPC1 has shown that NPC1 has two protruding loops (loops 1 and 2), which engage a hydrophobic pocket on the head of EBOV GPcl (Igarashi et al. 2021). Cholesterol docking studies, focusing on binding recognition, showed differences in the binding positions of mutant variants versus the wild-type protein (Martínez-Archundia et al. 2020).

Accession Number:O15118
Protein Name:NPC1 aka NPC
Length:1278
Molecular Weight:142167.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:13
Location1 / Topology2 / Orientation3: Late endosome membrane1 / Multi-pass membrane protein2
Substrate cholesterol, lipids

Cross database links:

RefSeq: NP_000262.2   
Entrez Gene ID: 4864   
Pfam: PF02460   
OMIM: 257220  phenotype
607623  gene
KEGG: hsa:4864   

Gene Ontology

GO:0005783 C:endoplasmic reticulum
GO:0005887 C:integral to plasma membrane
GO:0031902 C:late endosome membrane
GO:0005765 C:lysosomal membrane
GO:0005635 C:nuclear envelope
GO:0048471 C:perinuclear region of cytoplasm
GO:0008158 F:hedgehog receptor activity
GO:0005515 F:protein binding
GO:0015248 F:sterol transporter activity
GO:0008206 P:bile acid metabolic process
GO:0033344 P:cholesterol efflux
GO:0042632 P:cholesterol homeostasis
GO:0007041 P:lysosomal transport

References (23)

[1] “Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis.”  Carstea E.D.et.al.   9211849
[2] “The genomic organization and polymorphism analysis of the human Niemann-Pick C1 gene.”  Morris J.A.et.al.   10425213
[3] “NPC1: complete genomic sequence, mutation analysis, and characterization of haplotypes.”  Bauer P.et.al.   11754101
[4] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[5] “Niemann-Pick C1 protein: obligatory roles for N-terminal domains and lysosomal targeting in cholesterol mobilization.”  Watari H.et.al.   9927649
[6] “Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry.”  Chen R.et.al.   19159218
[7] “The Nova Scotia (type D) form of Niemann-Pick disease is caused by a G3097-->T transversion in NPC1.”  Greer W.L.et.al.   9634529
[8] “Mutations in NPC1 highlight a conserved NPC1-specific cysteine-rich domain.”  Greer W.L.et.al.   10521290
[9] “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.”  Millat G.et.al.   10521297
[10] “NPC1 gene mutations in Japanese patients with Niemann-Pick disease type C.”  Yamamoto T.et.al.   10480349
[11] “Genotype-phenotype relationship of Niemann-Pick disease type C: a possible correlation between clinical onset and levels of NPC1 protein in isolated skin fibroblasts.”  Yamamoto T.et.al.   11182931
[12] “Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1.”  Sun X.et.al.   11349231
[13] “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.”  Millat G.et.al.   11333381
[14] “Clinical-biochemical correlation in molecularly characterized patients with Niemann-Pick type C.”  Meiner V.et.al.   11545687
[15] “Niemann-Pick type C disease: NPC1 mutations associated with severe and mild cellular cholesterol trafficking alterations.”  Ribeiro I.et.al.   11479732
[16] “Identification of novel mutations in the NPC1 gene in German patients with Niemann-Pick C disease.”  Kaminski W.E.et.al.   12408188
[17] “Niemann-Pick type C disease: mutations of NPC1 gene and evidence of abnormal expression of some mutant alleles in fibroblasts.”  Tarugi P.et.al.   12401890
[18] “Defective endocytic trafficking of NPC1 and NPC2 underlying infantile Niemann-Pick type C disease.”  Blom T.S.et.al.   12554680
[19] “Identification of 58 novel mutations in Niemann-Pick disease type C: correlation with biochemical phenotype and importance of PTC1-like domains in NPC1.”  Park W.D.et.al.   12955717
[20] “Identification of 25 new mutations in 40 unrelated Spanish Niemann-Pick type C patients: genotype-phenotype correlations.”  Fernandez-Valero E.M.et.al.   16098014
[21] “Six novel NPC1 mutations in Chinese patients with Niemann-Pick disease type C.”  Yang C.-C.et.al.   15774455
[22] “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.”  Millat G.et.al.   16126423
[23] “Subclinical course of adult visceral Niemann-Pick type C1 disease. A rare or underdiagnosed disorder?”  Dvorakova L.et.al.   16802107
Structure:
3GKH   3GKI   3GKJ   3jd8   5i31   5F18   5F1B   5HNS   5JNX   5KWY   [...more]

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MTARGLALGL LLLLLCPAQV FSQSCVWYGE CGIAYGDKRY NCEYSGPPKP LPKDGYDLVQ 
61:	ELCPGFFFGN VSLCCDVRQL QTLKDNLQLP LQFLSRCPSC FYNLLNLFCE LTCSPRQSQF 
121:	LNVTATEDYV DPVTNQTKTN VKELQYYVGQ SFANAMYNAC RDVEAPSSND KALGLLCGKD 
181:	ADACNATNWI EYMFNKDNGQ APFTITPVFS DFPVHGMEPM NNATKGCDES VDEVTAPCSC 
241:	QDCSIVCGPK PQPPPPPAPW TILGLDAMYV IMWITYMAFL LVFFGAFFAV WCYRKRYFVS 
301:	EYTPIDSNIA FSVNASDKGE ASCCDPVSAA FEGCLRRLFT RWGSFCVRNP GCVIFFSLVF 
361:	ITACSSGLVF VRVTTNPVDL WSAPSSQARL EKEYFDQHFG PFFRTEQLII RAPLTDKHIY 
421:	QPYPSGADVP FGPPLDIQIL HQVLDLQIAI ENITASYDNE TVTLQDICLA PLSPYNTNCT 
481:	ILSVLNYFQN SHSVLDHKKG DDFFVYADYH THFLYCVRAP ASLNDTSLLH DPCLGTFGGP 
541:	VFPWLVLGGY DDQNYNNATA LVITFPVNNY YNDTEKLQRA QAWEKEFINF VKNYKNPNLT 
601:	ISFTAERSIE DELNRESDSD VFTVVISYAI MFLYISLALG HMKSCRRLLV DSKVSLGIAG 
661:	ILIVLSSVAC SLGVFSYIGL PLTLIVIEVI PFLVLAVGVD NIFILVQAYQ RDERLQGETL 
721:	DQQLGRVLGE VAPSMFLSSF SETVAFFLGA LSVMPAVHTF SLFAGLAVFI DFLLQITCFV 
781:	SLLGLDIKRQ EKNRLDIFCC VRGAEDGTSV QASESCLFRF FKNSYSPLLL KDWMRPIVIA 
841:	IFVGVLSFSI AVLNKVDIGL DQSLSMPDDS YMVDYFKSIS QYLHAGPPVY FVLEEGHDYT 
901:	SSKGQNMVCG GMGCNNDSLV QQIFNAAQLD NYTRIGFAPS SWIDDYFDWV KPQSSCCRVD 
961:	NITDQFCNAS VVDPACVRCR PLTPEGKQRP QGGDFMRFLP MFLSDNPNPK CGKGGHAAYS 
1021:	SAVNILLGHG TRVGATYFMT YHTVLQTSAD FIDALKKARL IASNVTETMG INGSAYRVFP 
1081:	YSVFYVFYEQ YLTIIDDTIF NLGVSLGAIF LVTMVLLGCE LWSAVIMCAT IAMVLVNMFG 
1141:	VMWLWGISLN AVSLVNLVMS CGISVEFCSH ITRAFTVSMK GSRVERAEEA LAHMGSSVFS 
1201:	GITLTKFGGI VVLAFAKSQI FQIFYFRMYL AMVLLGATHG LIFLPVLLSY IGPSVNKAKS 
1261:	CATEERYKGT ERERLLNF