| IED ID | IndEnz0002006588 |
| Enzyme Type ID | protease006588 |
| Protein Name |
NACHT, LRR and PYD domains-containing protein 1a allele 3 EC 3.4.-.- Cleaved into: NACHT, LRR and PYD domains-containing protein 1a, C-terminus Nlrp1a-CT ; NACHT, LRR and PYD domains-containing protein 1a, N-terminus Nlrp1a-NT |
| Gene Name | Nlrp1a Nlrp1 |
| Organism | Rattus norvegicus (Rat) |
| 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 Glires (Rodents and rabbits) Rodentia Myomorpha (mice and others) Muroidea Muridae Murinae Rattus Rattus norvegicus (Rat) |
| Enzyme Sequence | MGESQSKQESNTRVAQHGSQQDVDPTFQTKRALERERSSPQVEQSFLGQLQSLLGWSSTSKDVPLSQLIREMDHESRRHSHQSKKKLDRSEHISEGTIPEIYEKRKETISHTQSMEQKYLFQNFTKLLLLQKCCPGGSEKLVRESWHPCVPEEGGHMIEIQDLFDPNLDTEKKPQLVIIEGAAGIGKSTLARQVKRAWDEGQLYRDRFQHVFFFSCRELAQCKQLSLAELIAQGQEVPTAPTRQILSRPEKLLFILDGIDEPAWVLEDQNPELCVHWSQAQPVHTLLGSLLGKSILPEASLMLTARTTALQKLVPSLGQPHRVEVLGFSEFERKDYFYKYFAKERNTIIDFNLIGSIPVLLTLCEVPWVCWLLCTCLEKQMQQGEVLSLTSQTTTALCLKYLSLTIPGQHLSTQLRTLCSLAAEGICQRRTLFSKSDLCKQGLAEDAIATFLKIGVLQRQPSSLSYSFAHLCLQEFFAAMSYILEDSEEAHGDMGNDRTVETLVERYGRQNLFEAPTVRFLLGLLNTREMREMENIFACKFPWETKLKLLQSIIGEPFCQPCHLGLFHCLYENQEEELLTETMLCFPLTASGPNHMEATVFQTNVKRLVIQTDMELMVVTFCITFSHVRSLRLKGKGQQEYKLTAPAMVLYRWTPISEASWKVLFSNLKCTRNLEELDLSGNPLSYSAVRSLCTALRQPGCRLKTLWLVDCGLTSRCCSFLASMLSAHSRLAELDLRLNDLGDNGVRQLCEGLRNPACNLSILRLDQASLSEQVITELRALETKNPKLFISSTWMSHMTMPTENTDGEESLTSSKQQQQQSGDKHMEPLGTDDDFWGPSGPVSTEVVDRERNLYRVRLPMAGSYHCPSTGLHFVVTRAVTIEIGFCAWSQFLHETPLQHSHMVAGPLFDIKAEHGAVTAVCLPHFVSLQEGKVDSSLFHVAHFQDHGMVLETPARVEPHFAVLENPSFSPMGVLLRMIPAVGHFIPITSITLIYYRLYLEDITFHLYLVPNDCTIRKAIDEEELKFQFVRINKPPPVDALYVGSRYIVSSSKEVEILPKELELCYRSPRESQLFSEIYVGNIGSGINLQLTDKKYMNLIWEALLKPGDLRPALPRMASAPKDAPALLHFVDQHREQLVARVTSVDPLLDKLHGLVLSEEDYETVRAEATNQDKMRKLFRGSRSWSWDCKDHFYQALKETHPHLIMDLLEKSGGVSVRL |
| Enzyme Length | 1218 |
| Uniprot Accession Number | D9I2H0 |
| Absorption | |
| Active Site | |
| Activity Regulation | ACTIVITY REGULATION: Activated by pathogens and other damage-associated signals: activation 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 1a, C-terminus), which polymerizes and forms the Nlrp1a inflammasome (By similarity). Nlrp1a inflammasome is inhibited by DPP8 and DPP9, which sequester the C-terminal fragment of Nlrp1a (NACHT, LRR and PYD domains-containing protein 1a, C-terminus) in a ternary complex, thereby preventing Nlrp1a oligomerization and activation (By similarity). Nlrp1a inflammasome is strongly activated by Val-boroPro (Talabostat, PT-100), an inhibitor of dipeptidyl peptidases DPP8 and DPP9 (PubMed:31383852). Val-boroPro relieves inhibition of DPP8 and/or DPP9 by promoting disruption of the ternary complex, releasing its C-terminal part from autoinhibition (By similarity). Not activated by cleavage by B.anthracis lethal toxin (LT) endopeptidase (PubMed:20502689). {ECO:0000250|UniProtKB:D9I2F9, ECO:0000250|UniProtKB:Q2LKW6, ECO:0000269|PubMed:20502689, ECO:0000269|PubMed:31383852}. |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | |
| DNA Binding | |
| EC Number | 3.4.-.- |
| Enzyme Function | FUNCTION: Acts as the sensor component of the Nlrp1a inflammasome, which mediates inflammasome activation in response to various pathogen-associated signals, leading to subsequent pyroptosis (By similarity). 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 (By similarity). Acts as a recognition receptor (PRR): recognizes specific pathogens and other damage-associated signals, such as Val-boroPro inhibitor, and mediates the formation of the inflammasome polymeric complex (PubMed:31383852). In response to pathogen-associated signals, the N-terminal part of Nlrp1a is degraded by the proteasome, releasing the cleaved C-terminal part of the protein (NACHT, LRR and PYD domains-containing protein 1a, C-terminus), which polymerizes to initiate the formation of the inflammasome complex: the inflammasome directly recruits pro-caspase-1 (proCASP1) independently of PYCARD/ASC and promotes caspase-1 (CASP1) activation, which subsequently cleaves and activates inflammatory cytokines IL1B and IL18 and gasdermin-D (GSDMD), leading to pyroptosis (By similarity). {ECO:0000250|UniProtKB:Q2LKU9, ECO:0000250|UniProtKB:Q2LKW6, ECO:0000250|UniProtKB:Q9C000, ECO:0000269|PubMed:31383852}.; FUNCTION: [NACHT, LRR and PYD domains-containing protein 1a allele 3]: Constitutes the precursor of the Nlrp1a 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:0000250|UniProtKB:Q9C000}.; FUNCTION: [NACHT, LRR and PYD domains-containing protein 1a, N-terminus]: Regulatory part that prevents formation of the Nlrp1a inflammasome: in absence of pathogens and other damage-associated signals, interacts with the C-terminal part of Nlrp1a (NACHT, LRR and PYD domains-containing protein 1a, C-terminus), preventing activation of the Nlrp1a inflammasome. In response to pathogen-associated signals, this part is ubiquitinated by the N-end rule pathway and degraded by the proteasome, releasing the cleaved C-terminal part of the protein, which polymerizes and forms the Nlrp1a inflammasome. {ECO:0000250|UniProtKB:Q9C000}.; FUNCTION: [NACHT, LRR and PYD domains-containing protein 1a, C-terminus]: Constitutes the active part of the Nlrp1a inflammasome. In absence of pathogens and other damage-associated signals, interacts with the N-terminal part of Nlrp1a (NACHT, LRR and PYD domains-containing protein 1a, N-terminus), preventing activation of the Nlrp1a inflammasome. In response to pathogen-associated signals, the N-terminal part of Nlrp1a is degraded by the proteasome, releasing this form, which polymerizes to form the Nlrp1a inflammasome complex: the Nlrp1a inflammasome complex then directly recruits pro-caspase-1 (proCASP1) and promotes caspase-1 (CASP1) activation, leading to gasdermin-D (GSDMD) cleavage and subsequent pyroptosis. {ECO:0000250|UniProtKB:Q9C000}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | NP_BIND 181..188; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00136 |
| Features | Chain (3); Compositional bias (2); Domain (3); Nucleotide binding (1); Region (5); Repeat (3); Site (2) |
| Keywords | ATP-binding;Cytoplasm;Hydrolase;Immunity;Inflammasome;Inflammatory response;Innate immunity;Leucine-rich repeat;Necrosis;Nucleotide-binding;Nucleus;Protease;Repeat;Ubl conjugation |
| Interact With | |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000250|UniProtKB:Q9C000}. Cytoplasm {ECO:0000250|UniProtKB:Q9C000}. Nucleus {ECO:0000250|UniProtKB:Q9C000}.; SUBCELLULAR LOCATION: [NACHT, LRR and PYD domains-containing protein 1a, C-terminus]: Inflammasome {ECO:0000250|UniProtKB:Q9C000}. |
| Modified Residue | |
| Post Translational Modification | PTM: [NACHT, LRR and PYD domains-containing protein 1a allele 3]: Autocatalytically cleaved. Autocatalytic cleavage in FIIND region occurs constitutively, prior to activation signals, and is required for inflammasome activity (IL1B release), possibly by facilitating CASP1 binding. Both N- and C-terminal parts remain associated non-covalently. {ECO:0000250|UniProtKB:Q9C000}.; PTM: [NACHT, LRR and PYD domains-containing protein 1a, N-terminus]: Ubiquitinated 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 1a, C-terminus), which polymerizes and forms the Nlrp1a inflammasome. {ECO:0000250|UniProtKB:Q9C000}. |
| Signal Peptide | |
| Structure 3D | |
| Cross Reference PDB | - |
| Mapped Pubmed ID | 18068672; 22133203; 22479187; 24014157; 24076348; 24626226; 24699513; 25024200; 30120609; 33731929; |
| Motif | |
| Gene Encoded By | |
| Mass | 138,235 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda |