| IED ID | IndEnz0002010334 |
| Enzyme Type ID | protease010334 |
| Protein Name |
Dipeptidyl peptidase 9 DP9 EC 3.4.14.5 Dipeptidyl peptidase IV-related protein 2 DPRP-2 Dipeptidyl peptidase IX DPP IX Dipeptidyl peptidase-like protein 9 DPLP9 |
| Gene Name | DPP9 DPRP2 |
| 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 | MATTGTPTADRGDAAATDDPAARFQVQKHSWDGLRSIIHGSRKYSGLIVNKAPHDFQFVQKTDESGPHSHRLYYLGMPYGSRENSLLYSEIPKKVRKEALLLLSWKQMLDHFQATPHHGVYSREEELLRERKRLGVFGITSYDFHSESGLFLFQASNSLFHCRDGGKNGFMVSPMKPLEIKTQCSGPRMDPKICPADPAFFSFINNSDLWVANIETGEERRLTFCHQGLSNVLDDPKSAGVATFVIQEEFDRFTGYWWCPTASWEGSEGLKTLRILYEEVDESEVEVIHVPSPALEERKTDSYRYPRTGSKNPKIALKLAEFQTDSQGKIVSTQEKELVQPFSSLFPKVEYIARAGWTRDGKYAWAMFLDRPQQWLQLVLLPPALFIPSTENEEQRLASARAVPRNVQPYVVYEEVTNVWINVHDIFYPFPQSEGEDELCFLRANECKTGFCHLYKVTAVLKSQGYDWSEPFSPGEDEFKCPIKEEIALTSGEWEVLARHGSKIWVNEETKLVYFQGTKDTPLEHHLYVVSYEAAGEIVRLTTPGFSHSCSMSQNFDMFVSHYSSVSTPPCVHVYKLSGPDDDPLHKQPRFWASMMEAASCPPDYVPPEIFHFHTRSDVRLYGMIYKPHALQPGKKHPTVLFVYGGPQVQLVNNSFKGIKYLRLNTLASLGYAVVVIDGRGSCQRGLRFEGALKNQMGQVEIEDQVEGLQFVAEKYGFIDLSRVAIHGWSYGGFLSLMGLIHKPQVFKVAIAGAPVTVWMAYDTGYTERYMDVPENNQHGYEAGSVALHVEKLPNEPNRLLILHGFLDENVHFFHTNFLVSQLIRAGKPYQLQIYPNERHSIRCPESGEHYEVTLLHFLQEYL |
| Enzyme Length | 863 |
| Uniprot Accession Number | Q86TI2 |
| Absorption | |
| Active Site | ACT_SITE 730; /note=Charge relay system; /evidence=ECO:0000305|PubMed:30291141; ACT_SITE 808; /note=Charge relay system; /evidence=ECO:0000250|UniProtKB:Q6V1X1; ACT_SITE 840; /note=Charge relay system; /evidence=ECO:0000250|UniProtKB:Q6V1X1 |
| Activity Regulation | ACTIVITY REGULATION: Inhibited by the serine proteinase inhibitor 4-(2-aminoethyl)benzenesulphonyl fluoride (AEBSF), and by di-isopropylfluorophosphate (PubMed:12662155). Inhibited by Val-boroPro (Talabostat, PT-100), a non-selective inhibitor, which triggers pyroptosis in monocytes and macrophages (PubMed:27820798, PubMed:29967349, PubMed:32796818, PubMed:33731932). Val-boroPro inhibits activity by binding to the active site, mimicking a substrate-bound state, thereby displacing the C-terminal fragment of NLRP1, leading to activation of the NLRP1 inflammasome (PubMed:34019797, PubMed:33731932). In contrast, Val-boroPro does not directly displaces CARD8: it acts by promoting degradation of the N-terminal part of CARD8, leading to indirect disruption of the ternary complex (PubMed:34019797). {ECO:0000269|PubMed:12662155, ECO:0000269|PubMed:27820798, ECO:0000269|PubMed:29967349, ECO:0000269|PubMed:32796818, ECO:0000269|PubMed:33731932, ECO:0000269|PubMed:34019797}. |
| Binding Site | BINDING 730; /note="Val-boroPro; inhibitor; covalent"; /evidence="ECO:0000269|PubMed:33731932, ECO:0000269|PubMed:34019797, ECO:0007744|PDB:6X6C, ECO:0007744|PDB:7JN7" |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=Release of an N-terminal dipeptide, Xaa-Yaa-|-Zaa-, from a polypeptide, preferentially when Yaa is Pro, provided Zaa is neither Pro nor hydroxyproline.; EC=3.4.14.5; Evidence={ECO:0000269|PubMed:12662155, ECO:0000269|PubMed:15245913, ECO:0000269|PubMed:16475979, ECO:0000269|PubMed:19667070, ECO:0000269|PubMed:29382749, ECO:0000269|PubMed:30291141, ECO:0000269|PubMed:33731929}; |
| DNA Binding | |
| EC Number | 3.4.14.5 |
| Enzyme Function | FUNCTION: Dipeptidyl peptidase that cleaves off N-terminal dipeptides from proteins having a Pro or Ala residue at position 2 (PubMed:12662155, PubMed:16475979, PubMed:19667070, PubMed:29382749, PubMed:30291141, PubMed:33731929). Acts as a key inhibitor of caspase-1-dependent monocyte and macrophage pyroptosis in resting cells by preventing activation of NLRP1 and CARD8 (PubMed:27820798, PubMed:29967349, PubMed:30291141, PubMed:31525884, PubMed:32796818). Sequesters the cleaved C-terminal part of NLRP1 and CARD8, which respectively constitute the active part of the NLRP1 and CARD8 inflammasomes, in a ternary complex, thereby preventing their oligomerization and activation (PubMed:34019797, PubMed:33731929, PubMed:33731932). The dipeptidyl peptidase activity is required to suppress NLRP1 and CARD8; however, neither NLRP1 nor CARD8 are bona fide substrates of DPP9, suggesting the existence of substrate(s) required for NLRP1 and CARD8 inhibition (PubMed:33731929). {ECO:0000269|PubMed:12662155, ECO:0000269|PubMed:16475979, ECO:0000269|PubMed:19667070, ECO:0000269|PubMed:27820798, ECO:0000269|PubMed:29382749, ECO:0000269|PubMed:29967349, ECO:0000269|PubMed:30291141, ECO:0000269|PubMed:31525884, ECO:0000269|PubMed:32796818, ECO:0000269|PubMed:33731929, ECO:0000269|PubMed:33731932, ECO:0000269|PubMed:34019797}. |
| Temperature Dependency | |
| PH Dependency | BIOPHYSICOCHEMICAL PROPERTIES: pH dependence: Optimum pH is 7.5-8.5. Little activity below pH 6.5. {ECO:0000269|PubMed:12662155, ECO:0000269|PubMed:15245913}; |
| Pathway | |
| nucleotide Binding | |
| Features | Active site (3); Alternative sequence (2); Beta strand (53); Binding site (1); Chain (1); Erroneous gene model prediction (2); Erroneous initiation (5); Frameshift (1); Helix (18); Initiator methionine (1); Modified residue (1); Mutagenesis (6); Region (1); Sequence caution (2); Sequence conflict (6); Turn (11) |
| Keywords | 3D-structure;Acetylation;Alternative splicing;Aminopeptidase;Cytoplasm;Hydrolase;Nucleus;Protease;Reference proteome;Serine protease |
| Interact With | Itself; Q6NUP5; P46379-2; Q8WUW1; Q96A83-2; O75190-2; O14645; Q01658; P29692-2; Q06787-7; Q9Y5Q9; O14901; Q9BVL2; Q96CV9; Q06830; P14678-2; P49458; Q11203; Q13148; P14927 |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm, cytosol {ECO:0000269|PubMed:12662155, ECO:0000269|PubMed:15245913}.; SUBCELLULAR LOCATION: [Isoform 2]: Nucleus {ECO:0000269|PubMed:24562348}. |
| Modified Residue | MOD_RES 2; /note=N-acetylalanine; /evidence=ECO:0007744|PubMed:19413330 |
| Post Translational Modification | |
| Signal Peptide | |
| Structure 3D | Electron microscopy (4); X-ray crystallography (4) |
| Cross Reference PDB | 6EOQ; 6EOR; 6QZV; 6X6A; 6X6C; 7A3F; 7JKQ; 7JN7; |
| Mapped Pubmed ID | 16700509; 16704418; 18940951; 19268648; 19581630; 20043068; 20534982; 21622624; 21711053; 22001206; 22736146; 23152501; 23519473; 23608773; 23704821; 24072711; 25464020; 25486458; 26496610; 27682012; 27943262; 28893231; 32815200; 32998073; 33785922; |
| Motif | |
| Gene Encoded By | |
| Mass | 98,263 |
| Kinetics | BIOPHYSICOCHEMICAL PROPERTIES: Kinetic parameters: KM=161 uM for Ala-Pro-AMC {ECO:0000269|PubMed:12662155, ECO:0000269|PubMed:15245913}; KM=180 uM for Ala-Pro-AFC {ECO:0000269|PubMed:12662155, ECO:0000269|PubMed:15245913}; KM=222 uM for Gly-Pro-AMC {ECO:0000269|PubMed:29382749}; KM=122 uM for Lys-Pro-AMC {ECO:0000269|PubMed:29382749}; KM=72.6 uM for Trp-Pro-AMC {ECO:0000269|PubMed:29382749}; KM=96 uM for Val-Pro-AMC {ECO:0000269|PubMed:29382749}; Note=kcat is 121 sec(-1) with Gly-Pro-AMC substrate (PubMed:29382749). kcat is 52,6 sec(-1) with Lys-Pro-AMC substrate (PubMed:29382749). kcat is 54 sec(-1) with Asp-Pro-AMC substrate (PubMed:29382749). kcat is 40,3 sec(-1) with Trp-Pro-AMC substrate (PubMed:29382749). kcat is 79,9 sec(-1) with Val-Pro-AMC substrate (PubMed:29382749). {ECO:0000269|PubMed:29382749}; |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda | 3.4.13.19; |