ID   UBP4_PONAB              Reviewed;         963 AA.
AC   Q5RCD3;
DT   11-SEP-2007, integrated into UniProtKB/Swiss-Prot.
DT   21-DEC-2004, sequence version 1.
DT   24-JAN-2024, entry version 91.
DE   RecName: Full=Ubiquitin carboxyl-terminal hydrolase 4;
DE            EC=3.4.19.12 {ECO:0000250|UniProtKB:Q13107};
DE   AltName: Full=Deubiquitinating enzyme 4;
DE   AltName: Full=Ubiquitin thioesterase 4;
DE   AltName: Full=Ubiquitin-specific-processing protease 4;
GN   Name=USP4;
OS   Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Pongo.
OX   NCBI_TaxID=9601;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain cortex;
RG   The German cDNA consortium;
RL   Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
CC   -!- FUNCTION: Deubiquitinating enzyme that removes conjugated ubiquitin
CC       from target proteins. Deubiquitinates PDPK1. Deubiquitinates TRIM21.
CC       Deubiquitinates receptor ADORA2A which increases the amount of
CC       functional receptor at the cell surface. Deubiquitinates HAS2.
CC       Deubiquitinates RHEB in response to EGF signaling, promoting mTORC1
CC       signaling. May regulate mRNA splicing through deubiquitination of the
CC       U4 spliceosomal protein PRPF3. This may prevent its recognition by the
CC       U5 component PRPF8 thereby destabilizing interactions within the
CC       U4/U6.U5 snRNP. May also play a role in the regulation of quality
CC       control in the ER. {ECO:0000250|UniProtKB:Q13107}.
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:0000250|UniProtKB:Q13107};
CC   -!- ACTIVITY REGULATION: The completion of the deubiquitinase reaction is
CC       mediated by the DUSP and ubiquitin-like 1 domains which promotes the
CC       release of ubiquitin from the catalytic site enabling subsequent
CC       reactions to occur. {ECO:0000250|UniProtKB:Q13107}.
CC   -!- SUBUNIT: Interacts with RB1 (both dephosphorylated and
CC       hypophosphorylated forms) (By similarity). Interacts with RBL1 and RBL2
CC       (By similarity). Interacts with ADORA2A (via cytoplasmic C-terminus);
CC       the interaction is direct. Interacts with SART3; recruits USP4 to its
CC       substrate PRPF3 (By similarity). {ECO:0000250|UniProtKB:P35123,
CC       ECO:0000250|UniProtKB:Q13107}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P35123,
CC       ECO:0000250|UniProtKB:Q13107}. Nucleus {ECO:0000250|UniProtKB:P35123,
CC       ECO:0000250|UniProtKB:Q13107}. Note=Shuttles between the nucleus and
CC       cytoplasm. Exported to the cytoplasm in a CRM1-dependent manner and
CC       recycled back to the nucleus via the importin alpha/beta heterodimeric
CC       import receptor. The relative amounts found in the nucleus and
CC       cytoplasm vary according to the cell type.
CC       {ECO:0000250|UniProtKB:P35123, ECO:0000250|UniProtKB:Q13107}.
CC   -!- DOMAIN: The DUSP and ubiquitin-like 1 domains promote ubiquitin release
CC       and thus enhance USB4 catalytic activity. However, these domains do not
CC       bind ubiquitin. {ECO:0000250|UniProtKB:Q13107}.
CC   -!- PTM: Phosphorylated at Ser-445 by PKB/AKT1 in response to EGF stimulus,
CC       promoting its ability deubiquitinate RHEB.
CC       {ECO:0000250|UniProtKB:Q13107}.
CC   -!- PTM: Monoubiquitinated by TRIM21. Ubiquitination does not lead to its
CC       proteasomal degradation. Autodeubiquitinated.
CC       {ECO:0000250|UniProtKB:Q13107}.
CC   -!- SIMILARITY: Belongs to the peptidase C19 family. USP4 subfamily.
CC       {ECO:0000305}.
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DR   EMBL; CR858339; CAH90574.1; -; mRNA.
DR   RefSeq; NP_001125307.1; NM_001131835.1.
DR   AlphaFoldDB; Q5RCD3; -.
DR   SMR; Q5RCD3; -.
DR   STRING; 9601.ENSPPYP00000015523; -.
DR   MEROPS; C19.010; -.
DR   GeneID; 100172206; -.
DR   KEGG; pon:100172206; -.
DR   CTD; 7375; -.
DR   eggNOG; KOG1870; Eukaryota.
DR   InParanoid; Q5RCD3; -.
DR   OrthoDB; 5474185at2759; -.
DR   Proteomes; UP000001595; Unplaced.
DR   GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR   GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR   GO; GO:0004843; F:cysteine-type deubiquitinase activity; ISS:UniProtKB.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0031397; P:negative regulation of protein ubiquitination; ISS:UniProtKB.
DR   GO; GO:1904263; P:positive regulation of TORC1 signaling; ISS:UniProtKB.
DR   GO; GO:0016579; P:protein deubiquitination; ISS:UniProtKB.
DR   GO; GO:0034394; P:protein localization to cell surface; ISS:UniProtKB.
DR   GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR   GO; GO:0031647; P:regulation of protein stability; ISS:UniProtKB.
DR   GO; GO:0000244; P:spliceosomal tri-snRNP complex assembly; ISS:UniProtKB.
DR   CDD; cd02674; Peptidase_C19R; 1.
DR   Gene3D; 3.90.70.10; Cysteine proteinases; 2.
DR   Gene3D; 3.30.2230.10; DUSP-like; 1.
DR   InterPro; IPR035927; DUSP-like_sf.
DR   InterPro; IPR038765; Papain-like_cys_pep_sf.
DR   InterPro; IPR006615; Pept_C19_DUSP.
DR   InterPro; IPR001394; Peptidase_C19_UCH.
DR   InterPro; IPR028135; Ub_USP-typ.
DR   InterPro; IPR018200; USP_CS.
DR   InterPro; IPR028889; USP_dom.
DR   PANTHER; PTHR21646; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE; 1.
DR   PANTHER; PTHR21646:SF45; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE 4; 1.
DR   Pfam; PF06337; DUSP; 1.
DR   Pfam; PF14836; Ubiquitin_3; 1.
DR   Pfam; PF00443; UCH; 1.
DR   SMART; SM00695; DUSP; 1.
DR   SUPFAM; SSF54001; Cysteine proteinases; 1.
DR   SUPFAM; SSF143791; DUSP-like; 1.
DR   PROSITE; PS51283; DUSP; 1.
DR   PROSITE; PS00972; USP_1; 1.
DR   PROSITE; PS00973; USP_2; 1.
DR   PROSITE; PS50235; USP_3; 1.
PE   2: Evidence at transcript level;
KW   Cytoplasm; Hydrolase; Metal-binding; Nucleus; Phosphoprotein; Protease;
KW   Reference proteome; Repeat; Thiol protease; Ubl conjugation;
KW   Ubl conjugation pathway; Zinc.
FT   CHAIN           1..963
FT                   /note="Ubiquitin carboxyl-terminal hydrolase 4"
FT                   /id="PRO_0000301667"
FT   DOMAIN          11..122
FT                   /note="DUSP"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00613"
FT   DOMAIN          142..226
FT                   /note="Ubiquitin-like 1"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          302..923
FT                   /note="USP"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01035"
FT   DOMAIN          483..571
FT                   /note="Ubiquitin-like 2"
FT                   /evidence="ECO:0000255"
FT   REGION          27..216
FT                   /note="Necessary for interaction with SART3"
FT                   /evidence="ECO:0000250|UniProtKB:Q13107"
FT   REGION          220..255
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          229..295
FT                   /note="Required for USP4 activation by providing
FT                   conformational flexibility between the DUSP and catalytic
FT                   domains"
FT                   /evidence="ECO:0000250|UniProtKB:Q13107"
FT   REGION          384..386
FT                   /note="Regulates ubiquitin dissociation"
FT                   /evidence="ECO:0000250|UniProtKB:Q13107"
FT   REGION          405..407
FT                   /note="Necessary for interaction with RBL2"
FT                   /evidence="ECO:0000250|UniProtKB:P35123"
FT   REGION          459..463
FT                   /note="Necessary for interaction with RB1 and RBL2"
FT                   /evidence="ECO:0000250|UniProtKB:P35123"
FT   REGION          485..775
FT                   /note="Interacts with DUSP and ubiquitin-like 1 domains and
FT                   is required for USP4 activation"
FT                   /evidence="ECO:0000250|UniProtKB:Q13107"
FT   REGION          637..698
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          928..963
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           133..141
FT                   /note="Nuclear export signal"
FT                   /evidence="ECO:0000250|UniProtKB:P35123"
FT   MOTIF           767..772
FT                   /note="Nuclear localization signal"
FT                   /evidence="ECO:0000250|UniProtKB:P35123"
FT   COMPBIAS        221..255
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        930..963
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        311
FT                   /note="Nucleophile"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01035"
FT   ACT_SITE        881
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01035"
FT   BINDING         461
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:Q13107"
FT   BINDING         464
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:Q13107"
FT   BINDING         799
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:Q13107"
FT   BINDING         802
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:Q13107"
FT   MOD_RES         445
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q13107"
FT   MOD_RES         655
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:B2GUZ1"
FT   MOD_RES         675
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P35123"
FT   MOD_RES         680
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P35123"
SQ   SEQUENCE   963 AA;  108318 MW;  818FB26F04B5AD2D CRC64;
     MAEGGGCRER PDAETQKSEL GALMRTTLQR GAQWYLIDSR WFKQWKKYVG FGSWDMYNVG
     EHNLFPGPID NSGLFSDPES QTLKEHLIDE LDYVLVPTEA WNKLLNWYGC VEGQQPIVRK
     VVEHGLFVKH CKVEVYLLEL KLCENSDPTN VLSCHFSKAD TIATIEKEMR KLFNIPAERE
     ARLWNKYMSN TYEQLSKLDN TVQDAGLYLG QVLVIEPQNE DGTWPRQTLQ SKSSTAPSRN
     FTTSPKSSAS PYSSVSDSLI ANGDSTSTCG MHSSGVSRGG SGFSASYNCQ EPPSSHIQPG
     LCGLGNLGNT CFMNSALQCL SNTAPLTDYF LKDEYEAEIN RDNPLGMKGE IAEAYAELIK
     QMWSGRDAHV APRMFKTQVG RFAPQFSGYQ QQDSQELLAF LLDGLHEDLN RVKKKPYLEL
     KDANGRPDVV VAKEAWENHR LRNDSVIVDT FHGLFKSTLV CPECAKVSVT FDPFCYLTLP
     LPLKKDRVME VFLVPADPHC RPTQYRVTVP LMGAVSDLCE ALSRLSGIAA ENMVVADVYN
     HRFHKIFQMD EGLNHIMPRD DIFVYEVCST SVDGSECVTL PVYFRERKSR PSSTSSASAL
     YGQPLLLSVP KHKLTLESLY QAVCDRISRY VKQPLPDEFG SSPLEPGACN GSRNSCEGED
     EEEMEHQEEG KEQLSETEGS GEDEPGSDPS ETTQKKIKGQ PCPKRLFTFS LVNSYGTADI
     NSLAADGKLL KLNSRSTLAM DWDSETRSLY YDEQESEAYE KHVSMLQPQK KKKTTVALRD
     CIELFTTMET LGEHDPWYCP NCKKHQQATK KSDLWSLPKI LVVHLKRFSY NRYWRDKLDT
     VVEFPIRGLN MSEFVCNLSA RPYVYDLIAV SNHYGAMGVG HYTAYAKNKL NGKWYYFDDS
     NVSLASEDQI VTKAAYVLFY QRRDDEFYKT PSLSSSGSSD GGTRPSSSQQ GLGDDEACSM
     DTN
//