NLRC4

NLRC4
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	4KXF
Identifikatori
Aliasi	NLRC4
Vanjski ID-jevi	OMIM: 606831 MGI: 3036243 HomoloGene: 10924 GeneCards: NLRC4
Lokacija gena (čovjek)
Hrom.	Hromosom 2 (čovjek)
Kraj	32,265,732 bp
Lokacija gena (miš)
Hrom.	Hromosom 17 (miš)
Kraj	74,766,137 bp
Ontologija gena
Molekularna funkcija	• nucleotide binding; • protein homodimerization activity; • GO:0050372 aktivnost sa transferazom ubikvitina; • GO:0001948, GO:0016582 vezivanje za proteine; • ATP binding; • magnesium ion binding; • cysteine-type endopeptidase inhibitor activity involved in apoptotic process; • vezivanje identičnih proteina;
Ćelijska komponenta	• citoplazma; • citosol; • intracellular anatomical structure; • IPAF inflammasome complex; • jedro;
Biološki proces	• Piroptoza; • inhibition of cysteine-type endopeptidase activity involved in apoptotic process; • immune system process; • regulation of cysteine-type endopeptidase activity involved in apoptotic process; • mitotic spindle assembly; • regulation of signal transduction; • defense response to bacterium; • positive regulation of NF-kappaB transcription factor activity; • detection of bacterium; • activation of innate immune response; • positive regulation of apoptotic process; • inflammatory response; • protein homooligomerization; • activation of cysteine-type endopeptidase activity involved in apoptotic process; • GO:0097285 apoptoza; • protein ubiquitination; • regulation of apoptotic process; • Urođeni imunski sistem;
	Izvori:Amigo / QuickGO
Ortolozi
	58484
	268973
	ENSG00000091106
	ENSMUSG00000039193
	Q9NPP4
	Q3UP24
	NM_001199138; NM_001199139; NM_001302504; NM_021209
	NM_001033367
	NP_001186067; NP_001186068; NP_001289433; NP_067032
	NP_001028539
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

NLR porodice CARD sa proteinskim domenom 4 jest protein koji je kod ljudi kodiran genom NLRC4 sa hromosoma 2.^[5]^[6]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 1.024 aminokiseline, a molekulska težina 116.159 Da.^[6]

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
MNFIKDNSRA	LIQRMGMTVI	KQITDDLFVW	NVLNREEVNI	ICCEKVEQDA
ARGIIHMILK	KGSESCNLFL	KSLKEWNYPL	FQDLNGQSLF	HQTSEGDLDD
LAQDLKDLYH	TPSFLNFYPL	GEDIDIIFNL	KSTFTEPVLW	RKDQHHHRVE
QLTLNGLLQA	LQSPCIIEGE	SGKGKSTLLQ	RIAMLWGSGK	CKALTKFKFV
FFLRLSRAQG	GLFETLCDQL	LDIPGTIRKQ	TFMAMLLKLR	QRVLFLLDGY
NEFKPQNCPE	IEALIKENHR	FKNMVIVTTT	TECLRHIRQF	GALTAEVGDM
TEDSAQALIR	EVLIKELAEG	LLLQIQKSRC	LRNLMKTPLF	VVITCAIQMG
ESEFHSHTQT	TLFHTFYDLL	IQKNKHKHKG	VAASDFIRSL	DHCGDLALEG
VFSHKFDFEL	QDVSSVNEDV	LLTTGLLCKY	TAQRFKPKYK	FFHKSFQEYT
AGRRLSSLLT	SHEPEEVTKG	NGYLQKMVSI	SDITSTYSSL	LRYTCGSSVE
ATRAVMKHLA	AVYQHGCLLG	LSIAKRPLWR	QESLQSVKNT	TEQEILKAIN
INSFVECGIH	LYQESTSKSA	LSQEFEAFFQ	GKSLYINSGN	IPDYLFDFFE
HLPNCASALD	FIKLDFYGGA	MASWEKAAED	TGGIHMEEAP	ETYIPSRAVS
LFFNWKQEFR	TLEVTLRDFS	KLNKQDIRYL	GKIFSSATSL	RLQIKRCAGV
AGSLSLVLST	CKNIYSLMVE	ASPLTIEDER	HITSVTNLKT	LSIHDLQNQR
LPGGLTDSLG	NLKNLTKLIM	DNIKMNEEDA	IKLAEGLKNL	KKMCLFHLTH
LSDIGEGMDY	IVKSLSSEPC	DLEEIQLVSC	CLSANAVKIL	AQNLHNLVKL
SILDLSENYL	EKDGNEALHE	LIDRMNVLEQ	LTALMLPWGC	DVQGSLSSLL
KHLEEVPQLV	KLGLKNWRLT	DTEIRILGAF	FGKNPLKNFQ	QLNLAGNRVS
SDGWLAFMGV	FENLKQLVFF	DFSTKEFLPD	PALVRKLSQV	LSKLTFLQEA
RLVGWQFDDD	DLSVITGAFK	LVTA

Struktura

Protein NLRC4 je visoko konzeran među vrstama sisara. Ima homologiju sa Ced4 proteinom C. elegans. Sadrži N-terminalni CARD domen, centralni nukleotidni vezujući domen/NACHT domen i C-terminalno [[leuxcin-bogatoponavljanje bogato ponavljanje (LRR ) domena. Pripada porodici NLR proteina koja uključuje koaktivator transkripcije CIITA i kanonski inflamasomski protein NLRP3. Skraćeni mišji NLRC4 bio je prvi član ove porodice čija je kristalna struktura riješena.^[7]

Funkcija

NLRC4 je najbolje povezan sa pokretanjem formiranja inflamasoma. Za razliku od NLRP3, određene funkcije NLRC4 zavisne od inflamasoma mogu se obavljati nezavisno od skele inflamasoma ASC. Ljudski Ced4 homolozi uključuju APAF1, NOD1 (CARD4) i NOD2 (CARD15). Ovi proteini imaju najmanje 1 N-terminalni CARD domen, praćen centralno lociranim domenom za vezivanje nukleotida (NBD ili NACHT) i C-terminalnim regulatornim domenom, koji se nalazi samo kod sisara, a sadrži ili WD40 ponavljanje ili ponavljanja bogata leucinom (LRR-ove). CARD12 je član porodice Ced4 i može izazvati apoptozu.^[6]

Interakcije

Pokazalo se da NLRC4 reaguje sa NAIP-om (postoji jedan ljudski NAIP, ali miševi eksprimiraju najmanje 4 različita NAIP proteina). Interakcija NAIP/NLRC4 može odrediti specifičnost liganda.^[8] Aktivnost inflamasoma ovisna o NLRC4 aktivira CASP1.^[9] Pod određenim okolnostima, NLRC4 i NLRP3 mogu zauzeti isti kompleks inflamasoma.^[10]

Klinički značaj

Ljudi koji imaju aktivirajuće mutacije u NLRC4 mogu razviti autoupalni sindrom karakteriziran akutnom temperaturom, hepatitisom, vrlo visokim serumskim feritinom i drugim karakteristikama koje upućuju na Sindrom aktivacije makrofaga (MAS) . Neki pacijenti su također razvili potencijalno po život opasan enterokolitis koji je nestajao u ranom djetinjstvu.^[11]^[12] Kod ovih pacijenata, pronađeno je hronično i izvanredno povišenje serumskog IL-18, za razliku od pacijenata sa mutacijama NLRP3 koji razvijaju kriopirinu pridruženie periodične sindrome.^[11] Velika japanska porodica imala je mnogo blažu bolest povezanu sa urtikarijom izazvanom hladnoćom koju je uzrokovala dominantno naslijeđena mutacija NLRC4.^[13]

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000091106 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000039193 - Ensembl, maj 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Geddes BJ, Wang L, Huang WJ, Lavellee M, Manji GA, Brown M, Jurman M, Cao J, Morgenstern J, Merriam S, Glucksmann MA, DiStefano PS, Bertin J (Jun 2001). "Human CARD12 is a novel CED4/Apaf-1 family member that induces apoptosis". Biochemical and Biophysical Research Communications. 284 (1): 77–82. doi:10.1006/bbrc.2001.4928. PMID 11374873.
^ ^a ^b ^c "Entrez Gene: NLRC4 NLR family, CARD domain containing 4".
^ Hu Z, Yan C, Liu P, Huang Z, Ma R, Zhang C, Wang R, Zhang Y, Martinon F, Miao D, Deng H, Wang J, Chang J, Chai J (Jul 2013). "Crystal structure of NLRC4 reveals its autoinhibition mechanism". Science. 341 (6142): 172–5. Bibcode:2013Sci...341..172H. doi:10.1126/science.1236381. PMID 23765277. S2CID 12360722.
^ Kofoed EM, Vance RE (Sep 2011). "Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity". Nature. 477 (7366): 592–5. Bibcode:2011Natur.477..592K. doi:10.1038/nature10394. PMC 3184209. PMID 21874021.
^ Damiano JS, Oliveira V, Welsh K, Reed JC (Jul 2004). "Heterotypic interactions among NACHT domains: implications for regulation of innate immune responses". The Biochemical Journal. 381 (Pt 1): 213–9. doi:10.1042/BJ20031506. PMC 1133779. PMID 15107016.
^ Man SM, Hopkins LJ, Nugent E, Cox S, Glück IM, Tourlomousis P, Wright JA, Cicuta P, Monie TP, Bryant CE (maj 2014). "Inflammasome activation causes dual recruitment of NLRC4 and NLRP3 to the same macromolecular complex" (PDF). Proceedings of the National Academy of Sciences of the United States of America. 111 (20): 7403–8. Bibcode:2014PNAS..111.7403M. doi:10.1073/pnas.1402911111. PMC 4034195. PMID 24803432.^{[mrtav link]}
^ ^a ^b Canna SW, de Jesus AA, Gouni S, Brooks SR, Marrero B, Liu Y, DiMattia MA, Zaal KJ, Sanchez GA, Kim H, Chapelle D, Plass N, Huang Y, Villarino AV, Biancotto A, Fleisher TA, Duncan JA, O'Shea JJ, Benseler S, Grom A, Deng Z, Laxer RM, Goldbach-Mansky R (Oct 2014). "An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome". Nature Genetics. 46 (10): 1140–6. doi:10.1038/ng.3089. PMC 4177369. PMID 25217959.
^ Romberg N, Al Moussawi K, Nelson-Williams C, Stiegler AL, Loring E, Choi M, Overton J, Meffre E, Khokha MK, Huttner AJ, West B, Podoltsev NA, Boggon TJ, Kazmierczak BI, Lifton RP (Oct 2014). "Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation". Nature Genetics. 46 (10): 1135–9. doi:10.1038/ng.3066. PMC 4177367. PMID 25217960.
^ Kitamura A, Sasaki Y, Abe T, Kano H, Yasutomo K (Nov 2014). "An inherited mutation in NLRC4 causes autoinflammation in human and mice". The Journal of Experimental Medicine. 211 (12): 2385–96. doi:10.1084/jem.20141091. PMC 4235634. PMID 25385754.

Dopunska literatura

Poyet JL, Srinivasula SM, Tnani M, Razmara M, Fernandes-Alnemri T, Alnemri ES (Jul 2001). "Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1". The Journal of Biological Chemistry. 276 (30): 28309–13. doi:10.1074/jbc.C100250200. PMID 11390368.
Damiano JS, Stehlik C, Pio F, Godzik A, Reed JC (Jul 2001). "CLAN, a novel human CED-4-like gene". Genomics. 75 (1–3): 77–83. doi:10.1006/geno.2001.6579. PMID 11472070.
Fu WN, Bertoni F, Kelsey SM, McElwaine SM, Cotter FE, Newland AC, Jia L (Jan 2003). "Role of DNA methylation in the suppression of Apaf-1 protein in human leukaemia". Oncogene. 22 (3): 451–5. doi:10.1038/sj.onc.1206147. PMID 12545166.
Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J (Mar 2004). "NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder". Immunity. 20 (3): 319–25. doi:10.1016/S1074-7613(04)00046-9. PMID 15030775.
Damiano JS, Oliveira V, Welsh K, Reed JC (Jul 2004). "Heterotypic interactions among NACHT domains: implications for regulation of innate immune responses". The Biochemical Journal. 381 (Pt 1): 213–9. doi:10.1042/BJ20031506. PMC 1133779. PMID 15107016.
Damiano JS, Newman RM, Reed JC (Nov 2004). "Multiple roles of CLAN (caspase-associated recruitment domain, leucine-rich repeat, and NAIP CIIA HET-E, and TP1-containing protein) in the mammalian innate immune response". Journal of Immunology. 173 (10): 6338–45. doi:10.4049/jimmunol.173.10.6338. PMID 15528373.
Sadasivam S, Gupta S, Radha V, Batta K, Kundu TK, Swarup G (Jan 2005). "Caspase-1 activator Ipaf is a p53-inducible gene involved in apoptosis". Oncogene. 24 (4): 627–36. doi:10.1038/sj.onc.1208201. PMID 15580302.
Lu C, Wang A, Wang L, Dorsch M, Ocain TD, Xu Y (Jun 2005). "Nucleotide binding to CARD12 and its role in CARD12-mediated caspase-1 activation". Biochemical and Biophysical Research Communications. 331 (4): 1114–9. doi:10.1016/j.bbrc.2005.04.027. PMID 15882992.
Thalappilly S, Sadasivam S, Radha V, Swarup G (Jun 2006). "Involvement of caspase 1 and its activator Ipaf upstream of mitochondrial events in apoptosis". The FEBS Journal. 273 (12): 2766–78. doi:10.1111/j.1742-4658.2006.05293.x. PMID 16817903. S2CID 21214841.

Šablon:NOD-liki receptori

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000091106 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000039193 - 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.

[pmid11374873-5] Geddes BJ, Wang L, Huang WJ, Lavellee M, Manji GA, Brown M, Jurman M, Cao J, Morgenstern J, Merriam S, Glucksmann MA, DiStefano PS, Bertin J (Jun 2001). "Human CARD12 is a novel CED4/Apaf-1 family member that induces apoptosis". Biochemical and Biophysical Research Communications. 284 (1): 77–82. doi:10.1006/bbrc.2001.4928. PMID 11374873.

[entrez-6] "Entrez Gene: NLRC4 NLR family, CARD domain containing 4".

[7] Hu Z, Yan C, Liu P, Huang Z, Ma R, Zhang C, Wang R, Zhang Y, Martinon F, Miao D, Deng H, Wang J, Chang J, Chai J (Jul 2013). "Crystal structure of NLRC4 reveals its autoinhibition mechanism". Science. 341 (6142): 172–5. Bibcode:2013Sci...341..172H. doi:10.1126/science.1236381. PMID 23765277. S2CID 12360722.

[8] Kofoed EM, Vance RE (Sep 2011). "Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity". Nature. 477 (7366): 592–5. Bibcode:2011Natur.477..592K. doi:10.1038/nature10394. PMC 3184209. PMID 21874021.

[pmid15107016-9] Damiano JS, Oliveira V, Welsh K, Reed JC (Jul 2004). "Heterotypic interactions among NACHT domains: implications for regulation of innate immune responses". The Biochemical Journal. 381 (Pt 1): 213–9. doi:10.1042/BJ20031506. PMC 1133779. PMID 15107016.

[10] Man SM, Hopkins LJ, Nugent E, Cox S, Glück IM, Tourlomousis P, Wright JA, Cicuta P, Monie TP, Bryant CE (maj 2014). "Inflammasome activation causes dual recruitment of NLRC4 and NLRP3 to the same macromolecular complex" (PDF). Proceedings of the National Academy of Sciences of the United States of America. 111 (20): 7403–8. Bibcode:2014PNAS..111.7403M. doi:10.1073/pnas.1402911111. PMC 4034195. PMID 24803432.^{[mrtav link]}

[Canna_2014-11] Canna SW, de Jesus AA, Gouni S, Brooks SR, Marrero B, Liu Y, DiMattia MA, Zaal KJ, Sanchez GA, Kim H, Chapelle D, Plass N, Huang Y, Villarino AV, Biancotto A, Fleisher TA, Duncan JA, O'Shea JJ, Benseler S, Grom A, Deng Z, Laxer RM, Goldbach-Mansky R (Oct 2014). "An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome". Nature Genetics. 46 (10): 1140–6. doi:10.1038/ng.3089. PMC 4177369. PMID 25217959.

[12] Romberg N, Al Moussawi K, Nelson-Williams C, Stiegler AL, Loring E, Choi M, Overton J, Meffre E, Khokha MK, Huttner AJ, West B, Podoltsev NA, Boggon TJ, Kazmierczak BI, Lifton RP (Oct 2014). "Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation". Nature Genetics. 46 (10): 1135–9. doi:10.1038/ng.3066. PMC 4177367. PMID 25217960.

[13] Kitamura A, Sasaki Y, Abe T, Kano H, Yasutomo K (Nov 2014). "An inherited mutation in NLRC4 causes autoinflammation in human and mice". The Journal of Experimental Medicine. 211 (12): 2385–96. doi:10.1084/jem.20141091. PMC 4235634. PMID 25385754.

[5]

[6]

[1]

[2]

[3]

[4]

[7]

[8]

[9]

[10]

[11]

[12]

[13]