| IED ID | IndEnz0002011594 |
| Enzyme Type ID | protease011594 |
| Protein Name |
Ubiquitin carboxyl-terminal hydrolase 8 EC 3.4.19.12 Deubiquitinating enzyme 8 Ubiquitin isopeptidase Y hUBPy Ubiquitin thioesterase 8 Ubiquitin-specific-processing protease 8 |
| Gene Name | USP8 KIAA0055 UBPY |
| 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 | MPAVASVPKELYLSSSLKDLNKKTEVKPEKISTKSYVHSALKIFKTAEECRLDRDEERAYVLYMKYVTVYNLIKKRPDFKQQQDYFHSILGPGNIKKAVEEAERLSESLKLRYEEAEVRKKLEEKDRQEEAQRLQQKRQETGREDGGTLAKGSLENVLDSKDKTQKSNGEKNEKCETKEKGAITAKELYTMMTDKNISLIIMDARRMQDYQDSCILHSLSVPEEAISPGVTASWIEAHLPDDSKDTWKKRGNVEYVVLLDWFSSAKDLQIGTTLRSLKDALFKWESKTVLRNEPLVLEGGYENWLLCYPQYTTNAKVTPPPRRQNEEVSISLDFTYPSLEESIPSKPAAQTPPASIEVDENIELISGQNERMGPLNISTPVEPVAASKSDVSPIIQPVPSIKNVPQIDRTKKPAVKLPEEHRIKSESTNHEQQSPQSGKVIPDRSTKPVVFSPTLMLTDEEKARIHAETALLMEKNKQEKELRERQQEEQKEKLRKEEQEQKAKKKQEAEENEITEKQQKAKEEMEKKESEQAKKEDKETSAKRGKEITGVKRQSKSEHETSDAKKSVEDRGKRCPTPEIQKKSTGDVPHTSVTGDSGSGKPFKIKGQPESGILRTGTFREDTDDTERNKAQREPLTRARSEEMGRIVPGLPSGWAKFLDPITGTFRYYHSPTNTVHMYPPEMAPSSAPPSTPPTHKAKPQIPAERDREPSKLKRSYSSPDITQAIQEEEKRKPTVTPTVNRENKPTCYPKAEISRLSASQIRNLNPVFGGSGPALTGLRNLGNTCYMNSILQCLCNAPHLADYFNRNCYQDDINRSNLLGHKGEVAEEFGIIMKALWTGQYRYISPKDFKITIGKINDQFAGYSQQDSQELLLFLMDGLHEDLNKADNRKRYKEENNDHLDDFKAAEHAWQKHKQLNESIIVALFQGQFKSTVQCLTCHKKSRTFEAFMYLSLPLASTSKCTLQDCLRLFSKEEKLTDNNRFYCSHCRARRDSLKKIEIWKLPPVLLVHLKRFSYDGRWKQKLQTSVDFPLENLDLSQYVIGPKNNLKKYNLFSVSNHYGGLDGGHYTAYCKNAARQRWFKFDDHEVSDISVSSVKSSAAYILFYTSLGPRVTDVAT |
| Enzyme Length | 1118 |
| Uniprot Accession Number | P40818 |
| Absorption | |
| Active Site | ACT_SITE 786; /note="Nucleophile"; /evidence="ECO:0000255|PROSITE-ProRule:PRU10092, ECO:0000255|PROSITE-ProRule:PRU10093"; ACT_SITE 1067; /note="Proton acceptor"; /evidence="ECO:0000255|PROSITE-ProRule:PRU10092, ECO:0000255|PROSITE-ProRule:PRU10093" |
| 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:9628861}; |
| DNA Binding | |
| EC Number | 3.4.19.12 |
| Enzyme Function | FUNCTION: Hydrolase that can remove conjugated ubiquitin from proteins and therefore plays an important regulatory role at the level of protein turnover by preventing degradation. Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains. Catalytic activity is enhanced in the M phase. Involved in cell proliferation. Required to enter into S phase in response to serum stimulation. May regulate T-cell anergy mediated by RNF128 via the formation of a complex containing RNF128 and OTUB1. Probably regulates the stability of STAM2 and RASGRF1. Regulates endosomal ubiquitin dynamics, cargo sorting, membrane traffic at early endosomes, and maintenance of ESCRT-0 stability. The level of protein ubiquitination on endosomes is essential for maintaining the morphology of the organelle. Deubiquitinates EPS15 and controles tyrosine kinase stability. Removes conjugated ubiquitin from EGFR thus regulating EGFR degradation and downstream MAPK signaling. Involved in acrosome biogenesis through interaction with the spermatid ESCRT-0 complex and microtubules. Deubiquitinates BIRC6/bruce and KIF23/MKLP1. Deubiquitinates BACE1 which inhibits BACE1 lysosomal degradation and modulates BACE-mediated APP cleavage and amyloid-beta formation (PubMed:27302062). {ECO:0000269|PubMed:16520378, ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:18329369, ECO:0000269|PubMed:27302062, ECO:0000269|PubMed:9628861}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Active site (2); Alternative sequence (2); Beta strand (25); Chain (1); Compositional bias (8); Domain (3); Helix (31); Modified residue (8); Motif (1); Mutagenesis (1); Natural variant (9); Region (4); Sequence caution (2); Sequence conflict (3); Turn (6) |
| Keywords | 3D-structure;Alternative splicing;Cell cycle;Cell membrane;Cushing syndrome;Cytoplasm;Disease variant;Endosome;Hydrolase;Membrane;Nucleus;Phosphoprotein;Protease;Reference proteome;SH3-binding;Thiol protease;Ubl conjugation;Ubl conjugation pathway |
| Interact With | Q9HD42; Q7LBR1; Q96CF2; Q99814; Q16665; Q14596; P63104 |
| Induction | INDUCTION: Upon growth stimulation in starved human fibroblasts. Decreases in response to growth arrest induced by cell-cell contact. {ECO:0000269|PubMed:9628861}. |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. Endosome membrane {ECO:0000269|PubMed:16520378, ECO:0000269|PubMed:17711858}; Peripheral membrane protein {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral membrane protein {ECO:0000305}. |
| Modified Residue | MOD_RES 160; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163"; MOD_RES 392; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:23186163"; MOD_RES 400; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:23186163"; MOD_RES 452; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:23186163"; MOD_RES 577; /note="Phosphothreonine"; /evidence="ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"; MOD_RES 718; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"; MOD_RES 719; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:18669648"; MOD_RES 945; /note="Phosphothreonine"; /evidence="ECO:0000250|UniProtKB:Q80U87" |
| Post Translational Modification | PTM: Phosphorylation of Ser-718 is essential for interaction with YWHAE and for cytosol localization. Undergoes dephosphorylation at Ser-718 in the M phase. Tyrosine-phosphorylated in its N-terminal half in an EGFR-dependent manner. {ECO:0000250}.; PTM: Ubiquitinated. Inactive form is mostly monoubiquitinated, but polyubiquitination happens too. Ubiquitination is increased in EGF-stimulated cells. Ubiquitination of active form is undetectable, suggesting a possibility that USP8 deubiquitinates itself, thereby regulating its own function (By similarity). {ECO:0000250}. |
| Signal Peptide | |
| Structure 3D | NMR spectroscopy (1); X-ray crystallography (5) |
| Cross Reference PDB | 1WHB; 2A9U; 2GFO; 2GWF; 3N3K; 6F09; |
| Mapped Pubmed ID | 10982817; 12176364; 12773374; 14661020; 15161933; 15324660; 15778465; 17210635; 17353931; 17979178; 19302785; 19615732; 20495530; 21415856; 23287719; 23416715; 24255178; 24378640; 24828152; 25260751; 25675982; 26496610; 29473952; |
| Motif | MOTIF 405..413; /note=SH3-binding; /evidence=ECO:0000250 |
| Gene Encoded By | |
| Mass | 127,523 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda | 3.4.19.12; |