| IED ID | IndEnz0002006682 |
| Enzyme Type ID | protease006682 |
| Protein Name |
NACHT, LRR and PYD domains-containing protein 1a EC 3.4.-.- 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 1a, C-terminus Nlrp1a-CT ; NACHT, LRR and PYD domains-containing protein 1a, N-terminus Nlrp1a-NT |
| Gene Name | Nlrp1a Card7 Nalp1 Nalp1a Nlrp1 |
| Organism | Mus musculus (Mouse) |
| 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 Mus Mus Mus musculus (Mouse) |
| Enzyme Sequence | MEESQSKQESSTKVAQHEGQEDVDPTFKTKKLMEVELMKHRVQLERNLKLRTFPGARTKQVKEALYPLLTWSSKSKNLFQNFTKLLLFKKLCQRGSENLVRESWYPCVPEEEAHMIDIQDLFGPNLGTQKKPQLVIIEGAAGIGKSTLARLVKRAWKEGKLYRNDFHHVFFFSCRELAQYEQLSLAELIVQGQEVPTAPIRQILSHPEKLLFILDGIDEPAWVLADQNPELCLHWSQTQPVHTLLGSLLGKSILPGASFLLTTRTTALQKFIPSLEQPCQVEVLGFTLFERKNYFYKYFGKKKGGVTTFTLVKSNSALLTLCEVPWVCWLVCTCLKKQMEQGGELSLTSQTTTALCLKYLSLTIPGQHMRTQLRDLCSLAAEGVCQRRTLFSESDLCKQGLDEHAIASFLKIGVLQKQASSLSYSFAHLCLQEFFAAMSYILDDSEERHADMKNDRIVETLVERYGRQNLFEAPTVRFLFGLLSKEELKKIEKLFSCSLHGKTKLKLLWHILGKSQPHQPPCLGLLHCLYENQDMELLTHVMHDLQGTIVPGPDDLAHTVLQTNVKHLVIQTDMDLMVVTFCIKFCCHVRSLQLNRKVQQGHKFTAPGMVLYRWTPITDASWKIFFSNLKLARNLEELDLSGNPLSYYAVHSLCTTLRKRGCQLKTLWLVECGLTSTYCSLLASVLSARSSLTELDLQLNDLGDGGVKMLCEGLRNPACNLSILWLDQASLSDQVIAELRTLEAKNPKLLISSTWKPHVMVPTMNMDKEEVGDSQALLKQQRQQSGDKHMEPLGTEDEFWGPTGPVTTEVVDRERNLYRVQLPMAGSYHCPSTGLHFVVTRAVTIEIEFCAWSQYLDKTPLQQSHMVVGPLFDIKAEQGAVTAVYLPHFVALQEGIVDSSLFHVAHFQEHGMVLETPARVEQHYAVLENPSFSPMGILLRMIPAVGHFIPITSTTLIYYHLYLEDVTFHLYLVPNDCSIRKAIDDEEMKFQFVRINKPPPVDALYLGSRYIVSSSKLVEIIPKELELCYRSPGESQLFSEIDIGHMDSEIKLQIKDKRHMNLKWEALLKPGDLRPALPKIATAPKDAPSLLHFMDQHREQLVARVTSVDPLLDKLHGLVLSEDSYEVVRSETTNQDKMRKLFSLSRSWSWDCKDQFYQALKETHPHLVMDILEKLGGVSVKS |
| Enzyme Length | 1182 |
| Uniprot Accession Number | Q2LKU9 |
| Absorption | |
| Active Site | |
| Activity Regulation | ACTIVITY REGULATION: Nlrp1a inflammasome is 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 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). {ECO:0000250|UniProtKB:Q2LKW6, ECO:0000250|UniProtKB:Q9C000, 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 (PubMed:23219391). 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, and mediates the formation of the inflammasome polymeric complex (By similarity). 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 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 (By similarity). Activation of Nlrp1a inflammasome is also required for HMGB1 secretion; the active cytokines and HMGB1 stimulate inflammatory responses (By similarity). When activated in the bone marrow, induces the pyroptosis of hematopoietic stem cells and progenitor cells of both myeloid and lymphoid lineages, hence allowing the removal of damaged cells, and the release of IL1B, which induces granulopoiesis (PubMed:23219391). {ECO:0000250|UniProtKB:Q9C000, ECO:0000269|PubMed:23219391}.; FUNCTION: [NACHT, LRR and PYD domains-containing protein 1a]: 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 (By similarity). 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 Nlrp1a inflammasome (By similarity). {ECO:0000250|UniProtKB:Q9C000}.; FUNCTION: [NACHT, LRR and PYD domains-containing protein 1a, C-terminus]: Constitutes the active part of the Nlrp1a inflammasome (By similarity). 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 (By similarity). 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 (By similarity). {ECO:0000250|UniProtKB:Q9C000}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | NP_BIND 139..146; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00136 |
| Features | Alternative sequence (3); Chain (3); Domain (3); Mutagenesis (1); Natural variant (18); Nucleotide binding (1); Region (4); Repeat (3); Sequence conflict (1); Site (2) |
| Keywords | ATP-binding;Alternative splicing;Cytoplasm;Hydrolase;Immunity;Inflammasome;Inflammatory response;Innate immunity;Leucine-rich repeat;Necrosis;Nucleotide-binding;Nucleus;Protease;Reference proteome;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}. Note=Nucleocytoplasmic distribution in lymphoid organs (probably in T-cells) and in neurons. In epithelial cells, predominantly cytoplasmic. {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]: 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:0000305|PubMed:31383852}.; 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 | 12775719; 15967716; 18495787; 18511561; 19494813; 19924255; 21267068; 21677750; 22753929; 24008734; 24218483; 24337744; 24549849; 24606891; 24606892; 24699513; 25024200; 25681332; 25725098; 26434621; 26603191; 27199506; 27381056; 28733143; 30001530; 30214011; 30342528; 32421904; |
| Motif | |
| Gene Encoded By | |
| Mass | 134,308 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda |