UBP30_HUMAN
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 03-AUG-2022, entry version 157.
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 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};
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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 PDBsum; 5OHK; -.
DR PDBsum; 5OHN; -.
DR PDBsum; 5OHP; -.
DR AlphaFoldDB; Q70CQ3; -.
DR SMR; Q70CQ3; -.
DR BioGRID; 124238; 127.
DR DIP; DIP-53578N; -.
DR IntAct; Q70CQ3; 40.
DR MINT; Q70CQ3; -.
DR STRING; 9606.ENSP00000257548; -.
DR BindingDB; Q70CQ3; -.
DR ChEMBL; CHEMBL4523357; -.
DR MEROPS; C19.060; -.
DR iPTMnet; Q70CQ3; -.
DR PhosphoSitePlus; Q70CQ3; -.
DR BioMuta; USP30; -.
DR DMDM; 52000872; -.
DR EPD; Q70CQ3; -.
DR jPOST; Q70CQ3; -.
DR MassIVE; Q70CQ3; -.
DR MaxQB; Q70CQ3; -.
DR PaxDb; Q70CQ3; -.
DR PeptideAtlas; Q70CQ3; -.
DR PRIDE; Q70CQ3; -.
DR ProteomicsDB; 68524; -.
DR Antibodypedia; 1728; 179 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 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; CNETTTH; -.
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 1117 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 183 other tissues.
DR ExpressionAtlas; Q70CQ3; baseline and differential.
DR Genevisible; Q70CQ3; HS.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
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:0006511; P:ubiquitin-dependent protein catabolic process; IEA:InterPro.
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 Pfam; PF00443; UCH; 1.
DR SUPFAM; SSF54001; SSF54001; 1.
DR PROSITE; PS00972; USP_1; 1.
DR PROSITE; PS00973; USP_2; 1.
DR PROSITE; PS50235; USP_3; 1.
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 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
