| IED ID | IndEnz0002001449 |
| Enzyme Type ID | protease001449 |
| Protein Name |
NACHT, LRR and PYD domains-containing protein 1 EC 3.4.-.- EC 3.6.4.- Caspase recruitment domain-containing protein 7 Death effector filament-forming ced-4-like apoptosis protein Nucleotide-binding domain and caspase recruitment domain Cleaved into: NACHT, LRR and PYD domains-containing protein 1, C-terminus NLRP1-CT ; NACHT, LRR and PYD domains-containing protein 1, N-terminus NLRP1-NT |
| Gene Name | NLRP1 CARD7 DEFCAP KIAA0926 NAC NALP1 |
| Organism | Homo sapiens (Human) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
| Enzyme Sequence | MAGGAWGRLACYLEFLKKEELKEFQLLLANKAHSRSSSGETPAQPEKTSGMEVASYLVAQYGEQRAWDLALHTWEQMGLRSLCAQAQEGAGHSPSFPYSPSEPHLGSPSQPTSTAVLMPWIHELPAGCTQGSERRVLRQLPDTSGRRWREISASLLYQALPSSPDHESPSQESPNAPTSTAVLGSWGSPPQPSLAPREQEAPGTQWPLDETSGIYYTEIREREREKSEKGRPPWAAVVGTPPQAHTSLQPHHHPWEPSVRESLCSTWPWKNEDFNQKFTQLLLLQRPHPRSQDPLVKRSWPDYVEENRGHLIEIRDLFGPGLDTQEPRIVILQGAAGIGKSTLARQVKEAWGRGQLYGDRFQHVFYFSCRELAQSKVVSLAELIGKDGTATPAPIRQILSRPERLLFILDGVDEPGWVLQEPSSELCLHWSQPQPADALLGSLLGKTILPEASFLITARTTALQNLIPSLEQARWVEVLGFSESSRKEYFYRYFTDERQAIRAFRLVKSNKELWALCLVPWVSWLACTCLMQQMKRKEKLTLTSKTTTTLCLHYLAQALQAQPLGPQLRDLCSLAAEGIWQKKTLFSPDDLRKHGLDGAIISTFLKMGILQEHPIPLSYSFIHLCFQEFFAAMSYVLEDEKGRGKHSNCIIDLEKTLEAYGIHGLFGASTTRFLLGLLSDEGEREMENIFHCRLSQGRNLMQWVPSLQLLLQPHSLESLHCLYETRNKTFLTQVMAHFEEMGMCVETDMELLVCTFCIKFSRHVKKLQLIEGRQHRSTWSPTMVVLFRWVPVTDAYWQILFSVLKVTRNLKELDLSGNSLSHSAVKSLCKTLRRPRCLLETLRLAGCGLTAEDCKDLAFGLRANQTLTELDLSFNVLTDAGAKHLCQRLRQPSCKLQRLQLVSCGLTSDCCQDLASVLSASPSLKELDLQQNNLDDVGVRLLCEGLRHPACKLIRLGLDQTTLSDEMRQELRALEQEKPQLLIFSRRKPSVMTPTEGLDTGEMSNSTSSLKRQRLGSERAASHVAQANLKLLDVSKIFPIAEIAEESSPEVVPVELLCVPSPASQGDLHTKPLGTDDDFWGPTGPVATEVVDKEKNLYRVHFPVAGSYRWPNTGLCFVMREAVTVEIEFCVWDQFLGEINPQHSWMVAGPLLDIKAEPGAVEAVHLPHFVALQGGHVDTSLFQMAHFKEEGMLLEKPARVELHHIVLENPSFSPLGVLLKMIHNALRFIPVTSVVLLYHRVHPEEVTFHLYLIPSDCSIRKAIDDLEMKFQFVRIHKPPPLTPLYMGCRYTVSGSGSGMLEILPKELELCYRSPGEDQLFSEFYVGHLGSGIRLQVKDKKDETLVWEALVKPGDLMPATTLIPPARIAVPSPLDAPQLLHFVDQYREQLIARVTSVEVVLDKLHGQVLSQEQYERVLAENTRPSQMRKLFSLSQSWDRKCKDGLYQALKETHPHLIMELWEKGSKKGLLPLSS |
| Enzyme Length | 1473 |
| Uniprot Accession Number | Q9C000 |
| Absorption | |
| Active Site | |
| Activity Regulation | ACTIVITY REGULATION: NLRP1 inflammasome is activated by cleavage by human rhinoviruses 14 and 16 (HRV-14 and HRV-16): cleavage promotes ubiquitination and degradation of the N-terminal part, releasing the cleaved C-terminal part of the protein (NACHT, LRR and PYD domains-containing protein 1, C-terminus), which polymerizes and forms the NLRP1 inflammasome (PubMed:33093214). Activated double-stranded RNA: positive-strand RNA viruses such as Semliki forest virus and long dsRNA activate the NLRP1 inflammasome (PubMed:33243852). In contrast to its mouse ortholog, not activated by Bacillus anthracis lethal toxin (PubMed:19651869). NLRP1 inflammasome is inhibited by DPP8 and DPP9, which sequester the C-terminal fragment of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, C-terminus) in a ternary complex, thereby preventing NLRP1 oligomerization and activation (PubMed:30291141, PubMed:31525884, PubMed:33731929, PubMed:33731932). NLRP1 inflammasome is activated by Val-boroPro (Talabostat, PT-100), an inhibitor of dipeptidyl peptidases DPP8 and DPP9 (PubMed:30291141, PubMed:33731929, PubMed:33731932). Val-boroPro relieves inhibition of DPP8 and/or DPP9 by promoting disruption of the ternary complex, releasing its C-terminal part from autoinhibition (PubMed:33731929, PubMed:33731932). ATPase activity is activated by dsRNA-binding but not dsDNA-binding (PubMed:33243852). {ECO:0000269|PubMed:19651869, ECO:0000269|PubMed:30291141, ECO:0000269|PubMed:31525884, ECO:0000269|PubMed:33093214, ECO:0000269|PubMed:33243852, ECO:0000269|PubMed:33731929, ECO:0000269|PubMed:33731932}. |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; Evidence={ECO:0000269|PubMed:33243852};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:13066; Evidence={ECO:0000269|PubMed:33243852}; |
| DNA Binding | |
| EC Number | 3.4.-.-; 3.6.4.- |
| Enzyme Function | FUNCTION: Acts as the sensor component of the NLRP1 inflammasome, which mediates inflammasome activation in response to various pathogen-associated signals, leading to subsequent pyroptosis (PubMed:22665479, PubMed:12191486, PubMed:17349957, PubMed:27662089, PubMed:31484767, PubMed:33093214, PubMed:33731929, PubMed:33731932). Inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens and other damage-associated signals and play critical roles in innate immunity and inflammation (PubMed:22665479, PubMed:12191486, PubMed:17349957). Acts as a recognition receptor (PRR): recognizes specific pathogens and other damage-associated signals, such as cleavage by human rhinoviruses 14 and 16 (HRV-14 and HRV-16), double-stranded RNA or Val-boroPro inhibitor, and mediates the formation of the inflammasome polymeric complex composed of NLRP1, CASP1 and PYCARD/ASC (PubMed:22665479, PubMed:12191486, PubMed:17349957, PubMed:30291141, PubMed:33243852, PubMed:33093214). In response to pathogen-associated signals, the N-terminal part of NLRP1 is degraded by the proteasome, releasing the cleaved C-terminal part of the protein (NACHT, LRR and PYD domains-containing protein 1, C-terminus), which polymerizes and associates with PYCARD/ASC to initiate the formation of the inflammasome complex: the NLRP1 inflammasome recruits pro-caspase-1 (proCASP1) and promotes caspase-1 (CASP1) activation, which subsequently cleaves and activates inflammatory cytokines IL1B and IL18 and gasdermin-D (GSDMD), leading to pyroptosis (PubMed:22665479, PubMed:12191486, PubMed:17349957, PubMed:32051255, PubMed:33093214). Activation of NLRP1 inflammasome is also required for HMGB1 secretion; the active cytokines and HMGB1 stimulate inflammatory responses (PubMed:22801494). Binds ATP and shows ATPase activity (PubMed:11113115, PubMed:15212762, PubMed:33243852). Plays an important role in antiviral immunity and inflammation in the human airway epithelium (PubMed:33093214). Specifically recognizes a number of pathogen-associated signals: upon infection by human rhinoviruses 14 and 16 (HRV-14 and HRV-16), NLRP1 is cleaved and activated which triggers NLRP1-dependent inflammasome activation and IL18 secretion (PubMed:33093214). Positive-strand RNA viruses such as. Semliki forest virus and long dsRNA activate the NLRP1 inflammasome, triggering IL1B release in a NLRP1-dependent fashion (PubMed:33243852). Acts as a direct sensor for long dsRNA and thus RNA virus infection (PubMed:33243852). May also be activated by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan, in a NOD2-dependent manner (PubMed:18511561). {ECO:0000269|PubMed:11113115, ECO:0000269|PubMed:12191486, ECO:0000269|PubMed:15212762, ECO:0000269|PubMed:17349957, ECO:0000269|PubMed:18511561, ECO:0000269|PubMed:22665479, ECO:0000269|PubMed:22801494, ECO:0000269|PubMed:27662089, ECO:0000269|PubMed:30291141, ECO:0000269|PubMed:31484767, ECO:0000269|PubMed:32051255, ECO:0000269|PubMed:33093214, ECO:0000269|PubMed:33243852, ECO:0000269|PubMed:33731929, ECO:0000269|PubMed:33731932}.; FUNCTION: [NACHT, LRR and PYD domains-containing protein 1]: Constitutes the precursor of the NLRP1 inflammasome, which mediates autoproteolytic processing within the FIIND domain to generate the N-terminal and C-terminal parts, which are associated non-covalently in absence of pathogens and other damage-associated signals. {ECO:0000269|PubMed:22087307}.; FUNCTION: [NACHT, LRR and PYD domains-containing protein 1, N-terminus]: Regulatory part that prevents formation of the NLRP1 inflammasome: in absence of pathogens and other damage-associated signals, interacts with the C-terminal part of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, C-terminus), preventing activation of the NLRP1 inflammasome (PubMed:33093214). In response to pathogen-associated signals, this part is ubiquitinated and degraded by the proteasome, releasing the cleaved C-terminal part of the protein, which polymerizes and forms the NLRP1 inflammasome (PubMed:33093214). {ECO:0000269|PubMed:33093214}.; FUNCTION: [NACHT, LRR and PYD domains-containing protein 1, C-terminus]: Constitutes the active part of the NLRP1 inflammasome (PubMed:33093214, PubMed:33731929, PubMed:33731932). In absence of pathogens and other damage-associated signals, interacts with the N-terminal part of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, N-terminus), preventing activation of the NLRP1 inflammasome (PubMed:33093214). In response to pathogen-associated signals, the N-terminal part of NLRP1 is degraded by the proteasome, releasing this form, which polymerizes and associates with PYCARD/ASC to form of the NLRP1 inflammasome complex: the NLRP1 inflammasome complex then directly recruits pro-caspase-1 (proCASP1) and promotes caspase-1 (CASP1) activation, leading to gasdermin-D (GSDMD) cleavage and subsequent pyroptosis (PubMed:33093214). {ECO:0000269|PubMed:33093214, ECO:0000269|PubMed:33731929, ECO:0000269|PubMed:33731932}.; FUNCTION: [Isoform 2]: It is unclear whether is involved in inflammasome formation. It is not cleaved within the FIIND domain, does not assemble into specks, nor promote IL1B release (PubMed:22665479). However, in an vitro cell-free system, it has been shown to be activated by MDP (PubMed:17349957). {ECO:0000269|PubMed:17349957, ECO:0000269|PubMed:22665479}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | NP_BIND 334..341; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00136 |
| Features | Alternative sequence (7); Beta strand (11); Chain (3); Compositional bias (3); Domain (4); Erroneous initiation (1); Frameshift (1); Helix (20); Mutagenesis (66); Natural variant (17); Nucleotide binding (1); Region (5); Repeat (6); Sequence conflict (3); Site (3); Turn (1) |
| Keywords | 3D-structure;ATP-binding;Alternative splicing;Cytoplasm;Direct protein sequencing;Disease variant;Ectodermal dysplasia;Host-virus interaction;Hydrolase;Immunity;Inflammasome;Inflammatory response;Innate immunity;Leucine-rich repeat;Necrosis;Nucleotide-binding;Nucleus;Protease;Reference proteome;Repeat;Ubl conjugation |
| Interact With | P10415; Q07817; Q07817-1; P29466; Q9ULZ3 |
| Induction | INDUCTION: Up-regulated by ATF4 during endoplasmic reticulum (ER) stress response (PubMed:26086088). Up-regulated in arterial endothelial cells exposed to plasma from patients with peripheral arterial disease, but not to plasma from healthy controls (PubMed:24439873). {ECO:0000269|PubMed:24439873, ECO:0000269|PubMed:26086088}. |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:17418785}. Cytoplasm {ECO:0000269|PubMed:17164409}. Nucleus {ECO:0000269|PubMed:17164409}. Note=Nucleocytoplasmic distribution in lymphoid organs (probably in T-cells) and in neurons. In epithelial cells, predominantly cytoplasmic. {ECO:0000269|PubMed:17164409}.; SUBCELLULAR LOCATION: [NACHT, LRR and PYD domains-containing protein 1, C-terminus]: Inflammasome {ECO:0000269|PubMed:12191486, ECO:0000269|PubMed:22665479, ECO:0000269|PubMed:30291141, ECO:0000269|PubMed:33420028, ECO:0000269|PubMed:33420033}. |
| Modified Residue | |
| Post Translational Modification | PTM: [NACHT, LRR and PYD domains-containing protein 1]: Autocatalytically cleaved (PubMed:22087307, PubMed:22665479, PubMed:33093214). Autocatalytic cleavage in FIIND region occurs constitutively, prior to activation signals, and is required for inflammasome activity (IL1B release), possibly by facilitating CASP1 binding (PubMed:22087307, PubMed:22665479, PubMed:33093214). Both N- and C-terminal parts remain associated non-covalently (PubMed:22087307, PubMed:22665479, PubMed:33093214). {ECO:0000269|PubMed:22087307, ECO:0000269|PubMed:22665479, ECO:0000269|PubMed:33093214}.; PTM: [NACHT, LRR and PYD domains-containing protein 1, N-terminus]: Ubiquitinated by the cullin:ZER1/ZYG11B complex in response to pathogen-associated signals, leading to its degradation by the proteasome and subsequent release of the cleaved C-terminal part of the protein (NACHT, LRR and PYD domains-containing protein 1, C-terminus), which polymerizes and forms the NLRP1 inflammasome. {ECO:0000269|PubMed:33093214}.; PTM: (Microbial infection) Cleaved between Gln-130 and Gly-131 by human rhinovirus 14 (HRV-14) Protease 3C. This cleavage triggers N-glycine-mediated proteasomal degradation of the autoinhibitory NLRP1 N-terminal fragment via the cullin:ZER1/ZYG11B complex which liberates the activating C-terminal fragment and activates NLRP1 inflammasome. {ECO:0000269|PubMed:33093214}. |
| Signal Peptide | |
| Structure 3D | NMR spectroscopy (1); Electron microscopy (3); X-ray crystallography (4) |
| Cross Reference PDB | 1PN5; 3KAT; 4IFP; 4IM6; 5Y3S; 6K7V; 6X6C; 6XKK; |
| Mapped Pubmed ID | 14691733; 15174051; 17178784; 17620097; 17637824; 18263805; 18348116; 18946481; 19001869; 19074885; 19120479; 19223160; 19727120; 19913121; 20152874; 20370570; 20379614; 20403135; 20502346; 20574744; 20628086; 20711500; 20800603; 21098108; 21149496; 21245836; 21252346; 21331694; 21376416; 21946017; 21976003; 22117610; 22227487; 22235789; 22507623; 22524199; 23053059; 23253924; 23374100; 23380025; 23382179; 23508996; 23563199; 23773036; 23940760; 24008734; 24065540; 24334646; 24699513; 24909542; 25064844; 25342284; 25556596; 25611377; 25626361; 25725098; 25744023; 25814374; 26079697; 26232934; 26715049; 26902715; 26925775; 26939933; 27423725; 27626170; 27750030; 28263976; 28422993; 28503575; 28634744; 28653215; 28733143; 28808162; 28988323; 29031829; 29150951; 29214170; 29265930; 29393464; 29438387; 29528779; 29850521; 30096351; 30214011; 31078283; 31121538; 31293094; 31396539; 31601004; 31663353; 31694740; 32135277; 32922182; 33378691; 33385378; 33431827; 33658393; 33785922; 33854691; 33972620; |
| Motif | |
| Gene Encoded By | |
| Mass | 165,866 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | RHEA:13065; RHEA:13066 |
| Cross Reference Brenda |