| IED ID | IndEnz0002009277 |
| Enzyme Type ID | protease009277 |
| Protein Name |
Ubiquitin thioesterase otulin EC 3.4.19.12 Deubiquitinating enzyme otulin OTU domain-containing deubiquitinase with linear linkage specificity Ubiquitin thioesterase Gumby |
| Gene Name | OTULIN FAM105B |
| 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 | MSRGTMPQPEAWPGASCAETPAREAAATARDGGKAAASGQPRPEMQCPAEHEEDMYRAADEIEKEKELLIHERGASEPRLSVAPEMDIMDYCKKEWRGNTQKATCMKMGYEEVSQKFTSIRRVRGDNYCALRATLFQAMSQAVGLPPWLQDPELMLLPEKLISKYNWIKQWKLGLKFDGKNEDLVDKIKESLTLLRKKWAGLAEMRTAEARQIACDELFTNEAEEYSLYEAVKFLMLNRAIELYNDKEKGKEVPFFSVLLFARDTSNDPGQLLRNHLNQVGHTGGLEQVEMFLLAYAVRHTIQVYRLSKYNTEEFITVYPTDPPKDWPVVTLIAEDDRHYNIPVRVCEETSL |
| Enzyme Length | 352 |
| Uniprot Accession Number | Q96BN8 |
| Absorption | |
| Active Site | ACT_SITE 126; /evidence="ECO:0000269|PubMed:23708998, ECO:0000269|PubMed:23746843, ECO:0007744|PDB:3ZNZ, ECO:0007744|PDB:4KSL"; ACT_SITE 129; /note="Nucleophile"; /evidence="ECO:0000269|PubMed:23708998, ECO:0000269|PubMed:23746843, ECO:0000269|PubMed:24726327, ECO:0007744|PDB:3ZNZ, ECO:0007744|PDB:4KSL"; ACT_SITE 339; /evidence="ECO:0000269|PubMed:23708998, ECO:0000269|PubMed:23746843, ECO:0007744|PDB:3ZNZ, ECO:0007744|PDB:4KSL" |
| Activity Regulation | |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).; EC=3.4.19.12; Evidence={ECO:0000269|PubMed:23746843, ECO:0000269|PubMed:23827681, ECO:0000269|PubMed:27523608, ECO:0000269|PubMed:28919039}; |
| DNA Binding | |
| EC Number | 3.4.19.12 |
| Enzyme Function | FUNCTION: Deubiquitinase that specifically removes linear ('Met-1'-linked) polyubiquitin chains to substrates and acts as a regulator of angiogenesis and innate immune response (PubMed:26997266, PubMed:23708998, PubMed:23746843, PubMed:23806334, PubMed:23827681, PubMed:27523608, PubMed:27559085, PubMed:24726323, PubMed:24726327, PubMed:28919039). Required during angiogenesis, craniofacial and neuronal development by regulating the canonical Wnt signaling together with the LUBAC complex (PubMed:23708998). Acts as a negative regulator of NF-kappa-B by regulating the activity of the LUBAC complex (PubMed:23746843, PubMed:23806334). OTULIN function is mainly restricted to homeostasis of the LUBAC complex: acts by removing 'Met-1'-linked autoubiquitination of the LUBAC complex, thereby preventing inactivation of the LUBAC complex (PubMed:26670046). Acts as a key negative regulator of inflammation by restricting spontaneous inflammation and maintaining immune homeostasis (PubMed:27523608). In myeloid cell, required to prevent unwarranted secretion of cytokines leading to inflammation and autoimmunity by restricting linear polyubiquitin formation (PubMed:27523608). Plays a role in innate immune response by restricting linear polyubiquitin formation on LUBAC complex in response to NOD2 stimulation, probably to limit NOD2-dependent proinflammatory signaling (PubMed:23806334). {ECO:0000269|PubMed:23708998, ECO:0000269|PubMed:23746843, ECO:0000269|PubMed:23806334, ECO:0000269|PubMed:23827681, ECO:0000269|PubMed:24726323, ECO:0000269|PubMed:24726327, ECO:0000269|PubMed:26670046, ECO:0000269|PubMed:26997266, ECO:0000269|PubMed:27523608, ECO:0000269|PubMed:27559085, ECO:0000269|PubMed:28919039}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Active site (3); Beta strand (8); Chain (1); Domain (1); Erroneous initiation (3); Helix (18); Modified residue (1); Motif (1); Mutagenesis (14); Natural variant (5); Region (6); Sequence conflict (1); Site (1); Turn (1) |
| Keywords | 3D-structure;Acetylation;Angiogenesis;Cytoplasm;Disease variant;Hydrolase;Immunity;Innate immunity;Phosphoprotein;Protease;Reference proteome;Thiol protease;Ubl conjugation;Ubl conjugation pathway;Wnt signaling pathway |
| Interact With | Q15038; Q92567; Q92567-2; Q6GQQ9; Q8WV19; Q8N0X7; Q92537; Q8WW34-2 |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:23746843}. |
| Modified Residue | MOD_RES 56; /note="Phosphotyrosine"; /evidence="ECO:0000269|PubMed:24726323, ECO:0000269|PubMed:24726327" |
| Post Translational Modification | PTM: Ubiquitinated. {ECO:0000269|PubMed:23746843}.; PTM: Acetylated. {ECO:0000269|PubMed:23746843}.; PTM: Phosphorylated (PubMed:23746843, PubMed:24726323, PubMed:24726327). Phosphorylation at Tyr-56 prevents interaction with RNF31; dephosphorylation promotes interaction with RNF31 and the LUBAC complex (PubMed:24726323, PubMed:24726327). {ECO:0000269|PubMed:23746843, ECO:0000269|PubMed:24726323, ECO:0000269|PubMed:24726327}. |
| Signal Peptide | |
| Structure 3D | X-ray crystallography (11) |
| Cross Reference PDB | 3ZNV; 3ZNX; 3ZNZ; 4KSJ; 4KSK; 4KSL; 4OYK; 4P0B; 5OE7; 6I9C; 6SAK; |
| Mapped Pubmed ID | 16189514; 20379614; 20467437; 24461064; 25416956; 26235645; 28481361; 30804083; 31541095; 31825842; 32231246; 32543267; 32770022; 7851534; |
| Motif | MOTIF 52..57; /note="PIM motif"; /evidence="ECO:0000269|PubMed:24726323, ECO:0000269|PubMed:24726327, ECO:0000269|PubMed:27458237" |
| Gene Encoded By | |
| Mass | 40,263 |
| Kinetics | BIOPHYSICOCHEMICAL PROPERTIES: Kinetic parameters: KM=7.98 uM for linear diubiquitin {ECO:0000269|PubMed:23746843}; Note=kcat is 6.3 sec(-1) with linear diubiquitin as substrate. {ECO:0000269|PubMed:23746843}; |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda |