ID UBP30_HUMAN Reviewed; 517 AA. AC Q70CQ3; Q8WTU7; Q96JX4; Q9BSS3; DT 13-SEP-2004, integrated into UniProtKB/Swiss-Prot. DT 05-JUL-2004, sequence version 1. DT 27-MAR-2024, entry version 166. DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase 30; DE EC=3.4.19.12 {ECO:0000269|PubMed:14715245}; DE AltName: Full=Deubiquitinating enzyme 30; DE AltName: Full=Ubiquitin thioesterase 30; DE AltName: Full=Ubiquitin-specific-processing protease 30; DE Short=Ub-specific protease 30; GN Name=USP30 {ECO:0000312|HGNC:HGNC:20065}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND CATALYTIC ACTIVITY. RX PubMed=14715245; DOI=10.1016/j.bbrc.2003.12.050; RA Quesada V., Diaz-Perales A., Gutierrez-Fernandez A., Garabaya C., Cal S., RA Lopez-Otin C.; RT "Cloning and enzymatic analysis of 22 novel human ubiquitin-specific RT proteases."; RL Biochem. Biophys. Res. Commun. 314:54-62(2004). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Lung, and Skin; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 24-517. RC TISSUE=Placenta; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF ARG-28; LYS-30; LYS-33; RP 59-ARG--LYS-64 AND CYS-77, AND ACTIVE SITE. RX PubMed=18287522; DOI=10.1091/mbc.e07-11-1103; RA Nakamura N., Hirose S.; RT "Regulation of mitochondrial morphology by USP30, a deubiquitinating enzyme RT present in the mitochondrial outer membrane."; RL Mol. Biol. Cell 19:1903-1911(2008). RN [5] RP FUNCTION, SUBCELLULAR LOCATION, ACTIVE SITE, MUTAGENESIS OF CYS-77, AND RP UBIQUITINATION AT LYS-235 AND LYS-289. RX PubMed=24896179; DOI=10.1038/nature13418; RA Bingol B., Tea J.S., Phu L., Reichelt M., Bakalarski C.E., Song Q., RA Foreman O., Kirkpatrick D.S., Sheng M.; RT "The mitochondrial deubiquitinase USP30 opposes parkin-mediated RT mitophagy."; RL Nature 510:370-375(2014). RN [6] RP FUNCTION. RX PubMed=25527291; DOI=10.15252/embj.201489847; RA Wauer T., Swatek K.N., Wagstaff J.L., Gladkova C., Pruneda J.N., RA Michel M.A., Gersch M., Johnson C.M., Freund S.M., Komander D.; RT "Ubiquitin Ser65 phosphorylation affects ubiquitin structure, chain RT assembly and hydrolysis."; RL EMBO J. 34:307-325(2015). RN [7] RP FUNCTION, MUTAGENESIS OF CYS-77, AND ACTIVE SITE. RX PubMed=25621951; DOI=10.1038/ncb3097; RA Cunningham C.N., Baughman J.M., Phu L., Tea J.S., Yu C., Coons M., RA Kirkpatrick D.S., Bingol B., Corn J.E.; RT "USP30 and parkin homeostatically regulate atypical ubiquitin chains on RT mitochondria."; RL Nat. Cell Biol. 17:160-169(2015). CC -!- FUNCTION: Deubiquitinating enzyme tethered to the mitochondrial outer CC membrane that acts as a key inhibitor of mitophagy by counteracting the CC action of parkin (PRKN): hydrolyzes ubiquitin attached by parkin on CC target proteins, such as RHOT1/MIRO1 and TOMM20, thereby blocking CC parkin's ability to drive mitophagy (PubMed:18287522, PubMed:24896179, CC PubMed:25527291, PubMed:25621951). Preferentially cleaves 'Lys-6'- and CC 'Lys-11'-linked polyubiquitin chains, 2 types of linkage that CC participate in mitophagic signaling (PubMed:25621951). Does not cleave CC efficiently polyubiquitin phosphorylated at 'Ser-65' (PubMed:25527291). CC Acts as a negative regulator of mitochondrial fusion by mediating CC deubiquitination of MFN1 and MFN2 (By similarity). CC {ECO:0000250|UniProtKB:Q3UN04, ECO:0000269|PubMed:18287522, CC ECO:0000269|PubMed:24896179, ECO:0000269|PubMed:25527291, CC ECO:0000269|PubMed:25621951}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide CC and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76- CC residue protein attached to proteins as an intracellular targeting CC signal).; EC=3.4.19.12; Evidence={ECO:0000269|PubMed:14715245}; CC -!- ACTIVITY REGULATION: Inhibited by the diterpenoid derivative 15- CC oxospiramilactone (S3). {ECO:0000250|UniProtKB:Q3UN04}. CC -!- INTERACTION: CC Q70CQ3; P54253: ATXN1; NbExp=3; IntAct=EBI-2512374, EBI-930964; CC Q70CQ3; Q6NTF9-3: RHBDD2; NbExp=3; IntAct=EBI-2512374, EBI-17589229; CC -!- SUBCELLULAR LOCATION: Mitochondrion outer membrane CC {ECO:0000269|PubMed:18287522, ECO:0000269|PubMed:24896179}. CC -!- TISSUE SPECIFICITY: Expressed in skeletal muscle, pancreas, liver and CC kidney. {ECO:0000269|PubMed:14715245}. CC -!- PTM: Ubiquitinated by parkin (PRKN) at Lys-235 and Lys-289, leading to CC its degradation. {ECO:0000269|PubMed:24896179}. CC -!- SIMILARITY: Belongs to the peptidase C19 family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAH04868.1; Type=Erroneous initiation; Evidence={ECO:0000305}; CC Sequence=BAB55392.1; Type=Erroneous initiation; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AJ586136; CAE51936.1; -; mRNA. DR EMBL; BC004868; AAH04868.1; ALT_INIT; mRNA. DR EMBL; BC022094; AAH22094.2; -; mRNA. DR EMBL; AK027820; BAB55392.1; ALT_INIT; mRNA. DR CCDS; CCDS9123.2; -. DR RefSeq; NP_001288104.1; NM_001301175.1. DR RefSeq; NP_116052.2; NM_032663.4. DR RefSeq; XP_006719716.1; XM_006719653.3. DR PDB; 5OHK; X-ray; 2.34 A; A=64-178, A=217-357, A=432-502. DR PDB; 5OHN; X-ray; 3.60 A; A/C=64-357, A/C=432-502. DR PDB; 5OHP; X-ray; 2.80 A; A=64-178, A=217-357, A=432-502. DR PDB; 8D0A; X-ray; 3.19 A; A=64-178, A=190-357, A=432-502. DR PDB; 8D1T; X-ray; 2.94 A; A=64-178, A=190-357, A=432-502. DR PDBsum; 5OHK; -. DR PDBsum; 5OHN; -. DR PDBsum; 5OHP; -. DR PDBsum; 8D0A; -. DR PDBsum; 8D1T; -. DR AlphaFoldDB; Q70CQ3; -. DR SMR; Q70CQ3; -. DR BioGRID; 124238; 135. DR DIP; DIP-53578N; -. DR IntAct; Q70CQ3; 42. DR MINT; Q70CQ3; -. DR STRING; 9606.ENSP00000257548; -. DR BindingDB; Q70CQ3; -. DR ChEMBL; CHEMBL4523357; -. DR MEROPS; C19.060; -. DR iPTMnet; Q70CQ3; -. DR PhosphoSitePlus; Q70CQ3; -. DR SwissPalm; Q70CQ3; -. DR BioMuta; USP30; -. DR DMDM; 52000872; -. DR EPD; Q70CQ3; -. DR jPOST; Q70CQ3; -. DR MassIVE; Q70CQ3; -. DR MaxQB; Q70CQ3; -. DR PaxDb; 9606-ENSP00000257548; -. DR PeptideAtlas; Q70CQ3; -. DR ProteomicsDB; 68524; -. DR Pumba; Q70CQ3; -. DR Antibodypedia; 1728; 198 antibodies from 26 providers. DR DNASU; 84749; -. DR Ensembl; ENST00000257548.10; ENSP00000257548.5; ENSG00000135093.13. DR GeneID; 84749; -. DR KEGG; hsa:84749; -. DR MANE-Select; ENST00000257548.10; ENSP00000257548.5; NM_032663.5; NP_116052.2. DR UCSC; uc010sxi.3; human. DR AGR; HGNC:20065; -. DR CTD; 84749; -. DR DisGeNET; 84749; -. DR GeneCards; USP30; -. DR HGNC; HGNC:20065; USP30. DR HPA; ENSG00000135093; Low tissue specificity. DR MIM; 612492; gene. DR neXtProt; NX_Q70CQ3; -. DR OpenTargets; ENSG00000135093; -. DR PharmGKB; PA134971149; -. DR VEuPathDB; HostDB:ENSG00000135093; -. DR eggNOG; KOG1867; Eukaryota. DR GeneTree; ENSGT00550000075075; -. DR InParanoid; Q70CQ3; -. DR OMA; CEREGND; -. DR OrthoDB; 227085at2759; -. DR PhylomeDB; Q70CQ3; -. DR TreeFam; TF105781; -. DR PathwayCommons; Q70CQ3; -. DR Reactome; R-HSA-5689880; Ub-specific processing proteases. DR Reactome; R-HSA-9664873; Pexophagy. DR SignaLink; Q70CQ3; -. DR BioGRID-ORCS; 84749; 18 hits in 1195 CRISPR screens. DR ChiTaRS; USP30; human. DR GenomeRNAi; 84749; -. DR Pharos; Q70CQ3; Tchem. DR PRO; PR:Q70CQ3; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; Q70CQ3; Protein. DR Bgee; ENSG00000135093; Expressed in kidney epithelium and 185 other cell types or tissues. DR ExpressionAtlas; Q70CQ3; baseline and differential. DR GO; GO:0005829; C:cytosol; IBA:GO_Central. DR GO; GO:0005741; C:mitochondrial outer membrane; IDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; ISS:UniProtKB. DR GO; GO:0005634; C:nucleus; IBA:GO_Central. DR GO; GO:0005778; C:peroxisomal membrane; TAS:Reactome. DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:UniProtKB. DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IMP:UniProtKB. DR GO; GO:0101005; F:deubiquitinase activity; TAS:Reactome. DR GO; GO:0000422; P:autophagy of mitochondrion; IDA:UniProtKB. DR GO; GO:0008053; P:mitochondrial fusion; ISS:UniProtKB. DR GO; GO:1901525; P:negative regulation of mitophagy; IEA:Ensembl. DR GO; GO:0000425; P:pexophagy; TAS:Reactome. DR GO; GO:0016579; P:protein deubiquitination; IDA:UniProtKB. DR GO; GO:0035871; P:protein K11-linked deubiquitination; IDA:UniProtKB. DR GO; GO:0044313; P:protein K6-linked deubiquitination; IDA:UniProtKB. DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW. DR CDD; cd02662; Peptidase_C19F; 1. DR Gene3D; 3.90.70.10; Cysteine proteinases; 1. DR InterPro; IPR038765; Papain-like_cys_pep_sf. DR InterPro; IPR001394; Peptidase_C19_UCH. DR InterPro; IPR018200; USP_CS. DR InterPro; IPR028889; USP_dom. DR PANTHER; PTHR24006; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE; 1. DR PANTHER; PTHR24006:SF650; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE 30; 1. DR Pfam; PF00443; UCH; 1. DR SUPFAM; SSF54001; Cysteine proteinases; 1. DR PROSITE; PS00972; USP_1; 1. DR PROSITE; PS00973; USP_2; 1. DR PROSITE; PS50235; USP_3; 1. DR Genevisible; Q70CQ3; HS. PE 1: Evidence at protein level; KW 3D-structure; Hydrolase; Isopeptide bond; Membrane; Mitochondrion; KW Mitochondrion outer membrane; Protease; Reference proteome; Thiol protease; KW Transmembrane; Transmembrane helix; Ubl conjugation; KW Ubl conjugation pathway. FT CHAIN 1..517 FT /note="Ubiquitin carboxyl-terminal hydrolase 30" FT /id="PRO_0000080662" FT TOPO_DOM 1..35 FT /note="Mitochondrial intermembrane" FT /evidence="ECO:0000255" FT TRANSMEM 36..56 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 57..517 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 68..502 FT /note="USP" FT REGION 364..395 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 77 FT /note="Nucleophile" FT /evidence="ECO:0000269|PubMed:18287522, FT ECO:0000269|PubMed:24896179, ECO:0000269|PubMed:25621951" FT ACT_SITE 452 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10092, FT ECO:0000255|PROSITE-ProRule:PRU10093" FT CROSSLNK 235 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:24896179" FT CROSSLNK 289 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:24896179" FT VARIANT 357 FT /note="H -> R (in dbSNP:rs16939904)" FT /id="VAR_059751" FT MUTAGEN 28 FT /note="R->T: No change in mitochondrial subcellular FT location; when associated with N-30 and N-33." FT /evidence="ECO:0000269|PubMed:18287522" FT MUTAGEN 30 FT /note="K->N: No effect on subcellular location; when FT associated with N-28 and N-33." FT /evidence="ECO:0000269|PubMed:18287522" FT MUTAGEN 33 FT /note="K->N: No effect on subcellular location; when FT associated with N-28 and N-30." FT /evidence="ECO:0000269|PubMed:18287522" FT MUTAGEN 59..64 FT /note="RKKRRK->NNASNN: Loss of mitochondrial subcellular FT location. Located in the endoplasmic reticulum." FT /evidence="ECO:0000269|PubMed:18287522" FT MUTAGEN 77 FT /note="C->S: Loss of deubiquitinase activity and impaired FT ability to inhibit mitophagy. Increased TOMM20 FT ubiquitination." FT /evidence="ECO:0000269|PubMed:18287522, FT ECO:0000269|PubMed:24896179, ECO:0000269|PubMed:25621951" FT STRAND 73..75 FT /evidence="ECO:0007829|PDB:5OHK" FT HELIX 77..87 FT /evidence="ECO:0007829|PDB:5OHK" FT HELIX 90..100 FT /evidence="ECO:0007829|PDB:5OHK" FT HELIX 101..104 FT /evidence="ECO:0007829|PDB:5OHK" FT HELIX 116..127 FT /evidence="ECO:0007829|PDB:5OHK" FT HELIX 141..150 FT /evidence="ECO:0007829|PDB:5OHK" FT STRAND 156..158 FT /evidence="ECO:0007829|PDB:5OHK" FT HELIX 162..178 FT /evidence="ECO:0007829|PDB:5OHK" FT STRAND 226..234 FT /evidence="ECO:0007829|PDB:5OHK" FT TURN 235..237 FT /evidence="ECO:0007829|PDB:5OHK" FT STRAND 240..254 FT /evidence="ECO:0007829|PDB:5OHK" FT STRAND 259..261 FT /evidence="ECO:0007829|PDB:8D1T" FT HELIX 266..274 FT /evidence="ECO:0007829|PDB:5OHK" FT STRAND 277..282 FT /evidence="ECO:0007829|PDB:5OHK" FT STRAND 285..287 FT /evidence="ECO:0007829|PDB:5OHK" FT STRAND 306..316 FT /evidence="ECO:0007829|PDB:5OHK" FT STRAND 319..326 FT /evidence="ECO:0007829|PDB:5OHK" FT STRAND 328..330 FT /evidence="ECO:0007829|PDB:5OHK" FT STRAND 332..338 FT /evidence="ECO:0007829|PDB:5OHK" FT STRAND 347..350 FT /evidence="ECO:0007829|PDB:5OHK" FT HELIX 352..354 FT /evidence="ECO:0007829|PDB:5OHK" FT STRAND 355..357 FT /evidence="ECO:0007829|PDB:5OHK" FT STRAND 435..446 FT /evidence="ECO:0007829|PDB:5OHK" FT STRAND 448..450 FT /evidence="ECO:0007829|PDB:5OHK" FT STRAND 452..458 FT /evidence="ECO:0007829|PDB:5OHK" FT STRAND 463..465 FT /evidence="ECO:0007829|PDB:5OHP" FT STRAND 473..477 FT /evidence="ECO:0007829|PDB:5OHK" FT STRAND 480..484 FT /evidence="ECO:0007829|PDB:5OHK" FT HELIX 486..491 FT /evidence="ECO:0007829|PDB:5OHK" FT STRAND 494..502 FT /evidence="ECO:0007829|PDB:5OHK" SQ SEQUENCE 517 AA; 58503 MW; 68FA9B9BEBCFF8DF CRC64; MLSSRAEAAM TAADRAIQRF LRTGAAVRYK VMKNWGVIGG IAAALAAGIY VIWGPITERK KRRKGLVPGL VNLGNTCFMN SLLQGLSACP AFIRWLEEFT SQYSRDQKEP PSHQYLSLTL LHLLKALSCQ EVTDDEVLDA SCLLDVLRMY RWQISSFEEQ DAHELFHVIT SSLEDERDRQ PRVTHLFDVH SLEQQSEITP KQITCRTRGS PHPTSNHWKS QHPFHGRLTS NMVCKHCEHQ SPVRFDTFDS LSLSIPAATW GHPLTLDHCL HHFISSESVR DVVCDNCTKI EAKGTLNGEK VEHQRTTFVK QLKLGKLPQC LCIHLQRLSW SSHGTPLKRH EHVQFNEFLM MDIYKYHLLG HKPSQHNPKL NKNPGPTLEL QDGPGAPTPV LNQPGAPKTQ IFMNGACSPS LLPTLSAPMP FPLPVVPDYS SSTYLFRLMA VVVHHGDMHS GHFVTYRRSP PSARNPLSTS NQWLWVSDDT VRKASLQEVL SSSAYLLFYE RVLSRMQHQS QECKSEE //