NPC1

NPC1
Dostupne strukture PDB Pretraga ortologa: PDBe RCSB Spisak PDB ID kodova 3GKH, 3GKI, 3GKJ, 5F1B, 5F18, 5HNS, 3JD8, 5I31, 5JNX
Identifikatori
Aliasi	NPC1
Vanjski ID-jevi	OMIM: 607623 MGI: 1097712 HomoloGene: 228 GeneCards: NPC1
Lokacija gena (čovjek) Hrom. Hromosom 18 (čovjek)[1] Bend 18q11.2 Početak 23,506,184 bp[1] Kraj 23,586,506 bp[1]
Lokacija gena (miš) Hrom. Hromosom 18 (miš)[2] Bend 18 A1|18 6.15 cM Početak 12,322,749 bp[2] Kraj 12,369,457 bp[2]
Obrazac RNK ekspresije Više referentnih podataka o ekspresiji
Ontologija gena Molekularna funkcija • virus receptor activity • lipid transporter activity • sterol transporter activity • cholesterol binding • GO:0001948, GO:0016582 vezivanje za proteine • transmembrane signaling receptor activity • signaling receptor activity Ćelijska komponenta • integral component of membrane • Vezikula • endozom • Golđijev aparat • nuclear envelope • membrana • late endosome membrane • ćelijska membrana • integral component of plasma membrane • extracellular region • Endoplazmatski retikulum • perinuklearno područje citoplazme • Lipidni splav • Lizozom • Egzosom • lysosomal membrane • integral component of lysosomal membrane Biološki proces • cellular response to steroid hormone stimulus • steroid metabolic process • response to cadmium ion • Endocitoza • negative regulation of macroautophagy • lipid metabolism • bile acid metabolic process • cholesterol transport • establishment of protein localization to membrane • cellular response to low-density lipoprotein particle stimulus • cholesterol metabolic process • negative regulation of cell death • Autofagija • GO:0033578, GO:0033577, GO:0033575, GO:0033576 protein glycosylation • membrane raft organization • cholesterol efflux • lysosomal transport • viral entry into host cell • cholesterol homeostasis • GO:0022415 viral process • adult walking behavior • GO:0072468 Transdukcija signala • low-density lipoprotein particle clearance • intracellular cholesterol transport • lipid transport Izvori:Amigo / QuickGO
Ortolozi
Vrste	Čovjek	Miš
Entrez	4864	18145
Ensembl	ENSG00000141458	ENSMUSG00000024413
UniProt	O15118	O35604
RefSeq (mRNK)	NM_000271	NM_008720
RefSeq (bjelančevina)	NP_000262	NP_032746
Lokacija (UCSC)	Chr 18: 23.51 – 23.59 Mb	Chr 18: 12.32 – 12.37 Mb
PubMed pretraga	[3]	[4]
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/uredi – miš

Niemann-Pickova bolest tip C1 (NPC1) je bolest membranskog proteina koji kod sisara posreduje u unutarćelijsom prometu holesterola. Kod ljudi protein je kodiran genom NPC1, sa pozicijom 18q11.^[5][6]

Dužina polipeptidnog lanca je 1.278 aminokiselina, sa molekulsom težinom od 142.167^[7].

Aminokiselinska sekvenca

Simboli

C: Cistein
D: Asparaginska kiselina
E: Glutaminska kiselina
F: Fenilalanin
G: Glicin
H: Histidin
I: Izoleucin
K: Lizin
L: Leucin
M: Metionin
N: Asparagin
P: Prolin
Q: Glutamin
R: Arginin
S: Serin
T: Treonin
V: Valin
W: Triptofan
Y: Tirozin

10		20		30		40		50
MTARGLALGL		LLLLLCPAQV		FSQSCVWYGE		CGIAYGDKRY		NCEYSGPPKP
LPKDGYDLVQ		ELCPGFFFGN		VSLCCDVRQL		QTLKDNLQLP		LQFLSRCPSC
FYNLLNLFCE		LTCSPRQSQF		LNVTATEDYV		DPVTNQTKTN		VKELQYYVGQ
SFANAMYNAC		RDVEAPSSND		KALGLLCGKD		ADACNATNWI		EYMFNKDNGQ
APFTITPVFS		DFPVHGMEPM		NNATKGCDES		VDEVTAPCSC		QDCSIVCGPK
PQPPPPPAPW		TILGLDAMYV		IMWITYMAFL		LVFFGAFFAV		WCYRKRYFVS
EYTPIDSNIA		FSVNASDKGE		ASCCDPVSAA		FEGCLRRLFT		RWGSFCVRNP
GCVIFFSLVF		ITACSSGLVF		VRVTTNPVDL		WSAPSSQARL		EKEYFDQHFG
PFFRTEQLII		RAPLTDKHIY		QPYPSGADVP		FGPPLDIQIL		HQVLDLQIAI
ENITASYDNE		TVTLQDICLA		PLSPYNTNCT		ILSVLNYFQN		SHSVLDHKKG
DDFFVYADYH		THFLYCVRAP		ASLNDTSLLH		DPCLGTFGGP		VFPWLVLGGY
DDQNYNNATA		LVITFPVNNY		YNDTEKLQRA		QAWEKEFINF		VKNYKNPNLT
ISFTAERSIE		DELNRESDSD		VFTVVISYAI		MFLYISLALG		HMKSCRRLLV
DSKVSLGIAG		ILIVLSSVAC		SLGVFSYIGL		PLTLIVIEVI		PFLVLAVGVD
NIFILVQAYQ		RDERLQGETL		DQQLGRVLGE		VAPSMFLSSF		SETVAFFLGA
LSVMPAVHTF		SLFAGLAVFI		DFLLQITCFV		SLLGLDIKRQ		EKNRLDIFCC
VRGAEDGTSV		QASESCLFRF		FKNSYSPLLL		KDWMRPIVIA		IFVGVLSFSI
AVLNKVDIGL		DQSLSMPDDS		YMVDYFKSIS		QYLHAGPPVY		FVLEEGHDYT
SSKGQNMVCG		GMGCNNDSLV		QQIFNAAQLD		NYTRIGFAPS		SWIDDYFDWV
KPQSSCCRVD		NITDQFCNAS		VVDPACVRCR		PLTPEGKQRP		QGGDFMRFLP
MFLSDNPNPK		CGKGGHAAYS		SAVNILLGHG		TRVGATYFMT		YHTVLQTSAD
FIDALKKARL		IASNVTETMG		INGSAYRVFP		YSVFYVFYEQ		YLTIIDDTIF
NLGVSLGAIF		LVTMVLLGCE		LWSAVIMCAT		IAMVLVNMFG		VMWLWGISLN
AVSLVNLVMS		CGISVEFCSH		ITRAFTVSMK		GSRVERAEEA		LAHMGSSVFS
GITLTKFGGI		VVLAFAKSQI		FQIFYFRMYL		AMVLLGATHG		LIFLPVLLSY
IGPSVNKAKS		CATEERYKGT		ERERLLNF

Gen NPC1 nalazi se na dugom (q) kraku hromosoma 18, na poziciji q11.2.

Funkcija

NPC1 je identificiran kao gen čija mutacija izaziva Niemann-Pickovu bolest tip C. Niemann-Pick-ova bolest, tip C, rijedak je neurovisceralni poremećaj skladištenja lipida, koji je posljedica autosomnih recesivno naslijeđenih mutacija gubitka funkcije bilo u NPC1 ili NPC2. To remeti unutarćelijski transport lipida, što dovodi do akumulacije lipidnih produkata u kasnim endosomima i lizosomima. Otkriveno je da približno 95% NPC pacijenata ima mutacije u genu NPC1.

NPC1 kodira pretpostavljeni integralni membranski protein koji sadrži motiv sekvence u skladu s ulogom u unutarćelijskom transportu holesterola do odredišta nakon lizosoma.^[5][8]

Klinički značaj

Gojaznost

Mutacije u genu NPC1 snažno su povezane sa gojaznosti.^[9] Istraživanje povezanosti u genomu identificiralo je mutacije NPC1 kao faktor rizika kod dječje gojaznosti i morbidne gojaznosti odraslih i 1.416 starosne dobi odgovarajuće kontrole normalne težine.^[9] Mutacije u NPC1 također su bile u korelaciji sa uobičajenim prirastom težine u populaciji. Prethodne studije na miševima sugerirale su da gen NPC1 ima ulogu u kontroli apetita, budući da miševi s nefunkcionalnim genom NPC1 kasno počinju gubiti težinu i slabo unose hranu. Varijanta gena NPC1 mogla bi predstavljati oko 10 % ukupne dječje pretilosti i oko 14 % odraslih slučajeva morbidne pretilosti.^[9]

HIV-AIDS

Putevi holesterola imaju važnu ulogu u više faza tokom ciklusa infekcije HIV-1. Fuzija, ulazak, sastavljanje i pupanje HIV-1 dolazi do mikrodomena obogaćenih holesterolom, zvanih lipidni splav. Dokazano je da proteinski pribor za HIV-1, Nef, inducira mnoge gene koji su uključeni u biosintezu i homeostazu holesterola. Unutarćelijski putevi prometa holesterola, posredovani NPC1-om, potrebni su za efikasnu proizvodnju HIV-1.^[10][11]

Ebola virus

Čini se da je ljudski transporter holesterola Niemann-Pickove bolesti C1 (NPC1) ključan za infekciju virusom ebole: niz nezavisnih studija iznijele su dokaze da virus ebole ulazi u ljudske ćelije nakon vezanja za NPC1.^[12][13] Kada su ćelije pacijenata kojima ovaj transporter u laboratoriji nije bio izloženi virusu ebole, one su preživjele i izgledale nepropusno za virus, što dalje ukazuje da se ebola, za ulaz u ćelije, oslanja na NPC1.^[13] Iste studije su opisale slične rezultate sa Marburg virusom, drugim filovirusom, pokazujući da i njemu treba NPC1 za ulazak u ćelije.^[13] U jednoj od studija pokazalo se da je NPC1 presudan za ulazak u filovirusa, jer posreduje infekciju, vežući se direktno za glikoproteinsku virusnu ovojnicu.^[13] A kasnija studija potvrdila je nalaze da je NPC1 kritični filovirusni receptor koji posreduje infekciju, vežući se direktno za virusnu ovojnicu i da u ovom vezanju posreduje drugi lizosomski domen NPC1.^[14]

U jednoj od originalnih studija pokazano je da mala molekula inhibira infekciju virusom ebole, sprečavajući da se virusni glikoprotein veže za NPC1.^[13][15] U drugoj studiji pokazalo se da su heterozigotni miševi za NPC1 zaštićeni od smrtonosnog izazivanja za miševe prilagođenim virusom ebole.^[12] Zajedno, ove studije sugeriraju da NPC1 može biti potencijalni terapijski cilj za antivirusni lijek protiv ebole.

Mehanizmi u patologiji

U modelu miša koji nosi osnovnu mutaciju za Niemann–Pickovu bolest tip C1 u NPC1 proteinu, pokazalo se da je ekspresija regulatornog faktora mijelinskog gena (MRF) značajno smanjena.^[16] Regulatorni faktor gena za mijelin (MRF) je faktor transkripcije od presudne važnosti u razvoju i održavanju mijelinskih ovojnica.^[17] Perturbacija sazrijevanja oligodendrocita i proces mijelinizacije mogu stoga biti osnovni mehanizam neuroloških deficita.^[16]

Reference

1. GRCh38: Ensembl release 89: ENSG00000141458 - Ensembl, maj 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000024413 - Ensembl, maj 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: NPC1 Niemann-Pick disease, type C1".
6. Carstea ED, Polymeropoulos MH, Parker CC, Detera-Wadleigh SD, O'Neill RR, Patterson MC, et al. (mart 1993). "Linkage of Niemann-Pick disease type C to human chromosome 18". Proceedings of the National Academy of Sciences of the United States of America. 90 (5): 2002–4. Bibcode:1993PNAS...90.2002C. doi:10.1073/pnas.90.5.2002. PMC 46008. PMID 8446622.
7. "UniProt, O15118". Pristupljeno 12. 9. 2017.
8. Carstea ED, Morris JA, Coleman KG, Loftus SK, Zhang D, Cummings C, et al. (juli 1997). "Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis". Science. 277 (5323): 228–31. doi:10.1126/science.277.5323.228. PMID 9211849.
9. Meyre D, Delplanque J, Chèvre JC, Lecoeur C, Lobbens S, Gallina S, et al. (februar 2009). "Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations". Nature Genetics. 41 (2): 157–9. doi:10.1038/ng.301. PMID 19151714. S2CID 11218794.
10. Tang Y, Leao IC, Coleman EM, Broughton RS, Hildreth JE (august 2009). "Deficiency of niemann-pick type C-1 protein impairs release of human immunodeficiency virus type 1 and results in Gag accumulation in late endosomal/lysosomal compartments". Journal of Virology. 83 (16): 7982–95. doi:10.1128/JVI.00259-09. PMC 2715784. PMID 19474101.
11. Coleman EM, Walker TN, Hildreth JE (januar 2012). "Loss of Niemann Pick type C proteins 1 and 2 greatly enhances HIV infectivity and is associated with accumulation of HIV Gag and cholesterol in late endosomes/lysosomes". Virology Journal. 9 (1): 31. doi:10.1186/1743-422X-9-31. PMC 3299633. PMID 22273177.
12. Carette JE, Raaben M, Wong AC, Herbert AS, Obernosterer G, Mulherkar N, et al. (august 2011). "Ebola virus entry requires the cholesterol transporter Niemann-Pick C1". Nature. 477 (7364): 340–3. Bibcode:2011Natur.477..340C. doi:10.1038/nature10348. PMC 3175325. PMID 21866103. Sažetak – New York Times.
13. Côté M, Misasi J, Ren T, Bruchez A, Lee K, Filone CM, et al. (august 2011). "Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection". Nature. 477 (7364): 344–8. Bibcode:2011Natur.477..344C. doi:10.1038/nature10380. PMC 3230319. PMID 21866101. Sažetak – New York Times.
14. Miller EH, Obernosterer G, Raaben M, Herbert AS, Deffieu MS, Krishnan A, et al. (april 2012). "Ebola virus entry requires the host-programmed recognition of an intracellular receptor". The EMBO Journal. 31 (8): 1947–60. doi:10.1038/emboj.2012.53. PMC 3343336. PMID 22395071.
15. Flemming A (septembar 2011). "Achilles heel of Ebola viral entry". Nature Reviews. Drug Discovery. 10 (10): 731. doi:10.1038/nrd3568. PMID 21959282. S2CID 26888076.
16. Yan X, Lukas J, Witt M, Wree A, Hübner R, Frech M, et al. (decembar 2011). "Decreased expression of myelin gene regulatory factor in Niemann-Pick type C 1 mouse". Metabolic Brain Disease. 26 (4): 299–306. doi:10.1007/s11011-011-9263-9. PMID 21938520. S2CID 26878522.
17. Koenning M, Jackson S, Hay CM, Faux C, Kilpatrick TJ, Willingham M, Emery B (septembar 2012). "Myelin gene regulatory factor is required for maintenance of myelin and mature oligodendrocyte identity in the adult CNS". The Journal of Neuroscience. 32 (36): 12528–42. doi:10.1523/JNEUROSCI.1069-12.2012. PMC 3752083. PMID 22956843.

Dopunska literatura

• Vanier MT, Suzuki K (januar 1998). "Recent advances in elucidating Niemann-Pick C disease". Brain Pathology. 8 (1): 163–74. doi:10.1111/j.1750-3639.1998.tb00143.x. PMID 9458174. S2CID 10300500.
• Liscum L, Klansek JJ (april 1998). "Niemann-Pick disease type C". Current Opinion in Lipidology. 9 (2): 131–5. doi:10.1097/00041433-199804000-00009. PMID 9559270.
• Morris JA, Carstea ED (decembar 1998). "Niemann-Pick C disease: cholesterol handling gone awry". Molecular Medicine Today. 4 (12): 525–31. doi:10.1016/S1357-4310(98)01374-4. PMID 9866822.
• Garver WS, Heidenreich RA (august 2002). "The Niemann-Pick C proteins and trafficking of cholesterol through the late endosomal/lysosomal system". Current Molecular Medicine. 2 (5): 485–505. doi:10.2174/1566524023362375. PMID 12125814.
• Greer WL, Riddell DC, Byers DM, Welch JP, Girouard GS, Sparrow SM, et al. (juli 1997). "Linkage of Niemann-Pick disease type D to the same region of human chromosome 18 as Niemann-Pick disease type C". American Journal of Human Genetics. 61 (1): 139–42. doi:10.1086/513899. PMC 1715879. PMID 9245994.
• Greer WL, Riddell DC, Gillan TL, Girouard GS, Sparrow SM, Byers DM, et al. (juli 1998). "The Nova Scotia (type D) form of Niemann-Pick disease is caused by a G3097-->T transversion in NPC1". American Journal of Human Genetics. 63 (1): 52–4. doi:10.1086/301931. PMC 1377252. PMID 9634529.
• Watari H, Blanchette-Mackie EJ, Dwyer NK, Glick JM, Patel S, Neufeld EB, et al. (februar 1999). "Niemann-Pick C1 protein: obligatory roles for N-terminal domains and lysosomal targeting in cholesterol mobilization". Proceedings of the National Academy of Sciences of the United States of America. 96 (3): 805–10. Bibcode:1999PNAS...96..805W. doi:10.1073/pnas.96.3.805. PMC 15306. PMID 9927649.
• Patel SC, Suresh S, Kumar U, Hu CY, Cooney A, Blanchette-Mackie EJ, et al. (februar 1999). "Localization of Niemann-Pick C1 protein in astrocytes: implications for neuronal degeneration in Niemann- Pick type C disease". Proceedings of the National Academy of Sciences of the United States of America. 96 (4): 1657–62. Bibcode:1999PNAS...96.1657P. doi:10.1073/pnas.96.4.1657. PMC 15549. PMID 9990080.
• Morris JA, Zhang D, Coleman KG, Nagle J, Pentchev PG, Carstea ED (august 1999). "The genomic organization and polymorphism analysis of the human Niemann-Pick C1 gene". Biochemical and Biophysical Research Communications. 261 (2): 493–8. doi:10.1006/bbrc.1999.1070. PMID 10425213.
• Yamamoto T, Nanba E, Ninomiya H, Higaki K, Taniguchi M, Zhang H, et al. (1999). "NPC1 gene mutations in Japanese patients with Niemann-Pick disease type C". Human Genetics. 105 (1–2): 10–6. doi:10.1007/s004390051057. PMID 10480349.
• Greer WL, Dobson MJ, Girouard GS, Byers DM, Riddell DC, Neumann PE (novembar 1999). "Mutations in NPC1 highlight a conserved NPC1-specific cysteine-rich domain". American Journal of Human Genetics. 65 (5): 1252–60. doi:10.1086/302620. PMC 1288277. PMID 10521290.
• Millat G, Marçais C, Rafi MA, Yamamoto T, Morris JA, Pentchev PG, et al. (novembar 1999). "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". American Journal of Human Genetics. 65 (5): 1321–9. doi:10.1086/302626. PMC 1288284. PMID 10521297.
• Davies JP, Ioannou YA (august 2000). "Topological analysis of Niemann-Pick C1 protein reveals that the membrane orientation of the putative sterol-sensing domain is identical to those of 3-hydroxy-3-methylglutaryl-CoA reductase and sterol regulatory element binding protein cleavage-activating protein". The Journal of Biological Chemistry. 275 (32): 24367–74. doi:10.1074/jbc.M002184200. PMID 10821832.
• Millat G, Marçais C, Tomasetto C, Chikh K, Fensom AH, Harzer K, et al. (juni 2001). "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". American Journal of Human Genetics. 68 (6): 1373–85. doi:10.1086/320606. PMC 1226124. PMID 11333381.
• Sun X, Marks DL, Park WD, Wheatley CL, Puri V, O'Brien JF, et al. (juni 2001). "Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1". American Journal of Human Genetics. 68 (6): 1361–72. doi:10.1086/320599. PMC 1226123. PMID 11349231.

Vanjski linkovi

• NPC1 protein, human na US National Library of Medicine Medical Subject Headings (MeSH)
• Fight NPC, a website dedicated to providing information and resources on treating Niemann–Pick type C disease Arhivirano 5. 6. 2021. na Wayback Machine
• Hide & Seek Foundation for Lysosomal Disease Research