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Protein

Ubiquitin carboxyl-terminal hydrolase 46

Gene

USP46

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Deubiquitinating enzyme that plays a role in behavior, possibly by regulating GABA action. May act by mediating the deubiquitination of GAD1/GAD67 (By similarity). Has almost no deubiquitinating activity by itself and requires the interaction with WDR48 to have a high activity. Not involved in deubiquitination of monoubiquitinated FANCD2 (PubMed:19075014).By similarity1 Publication

Catalytic activityi

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).3 Publications

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Active sitei44 – 441NucleophilePROSITE-ProRule annotation1 Publication1 Publication
Active sitei313 – 3131Proton acceptorPROSITE-ProRule annotation

GO - Molecular functioni

  • thiol-dependent ubiquitin-specific protease activity Source: UniProtKB

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Protease, Thiol protease

Keywords - Biological processi

Behavior, Ubl conjugation pathway

Protein family/group databases

MEROPSiC19.052.

Names & Taxonomyi

Protein namesi
Recommended name:
Ubiquitin carboxyl-terminal hydrolase 46 (EC:3.4.19.123 Publications)
Alternative name(s):
Deubiquitinating enzyme 46
Ubiquitin thioesterase 46
Ubiquitin-specific-processing protease 46
Gene namesi
Name:USP46
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 4

Organism-specific databases

HGNCiHGNC:20075. USP46.

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi44 – 441C → S: Abolishes enzyme activity. 2 Publications

Organism-specific databases

PharmGKBiPA134922048.

Polymorphism and mutation databases

BioMutaiUSP46.
DMDMi49065850.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 366366Ubiquitin carboxyl-terminal hydrolase 46PRO_0000080674Add
BLAST

Proteomic databases

EPDiP62068.
MaxQBiP62068.
PaxDbiP62068.
PRIDEiP62068.

Expressioni

Tissue specificityi

Broadly expressed.1 Publication

Gene expression databases

BgeeiP62068.
CleanExiHS_USP46.
ExpressionAtlasiP62068. baseline and differential.
GenevisibleiP62068. HS.

Organism-specific databases

HPAiHPA007288.

Interactioni

Subunit structurei

Interacts with WDR48.2 Publications

Protein-protein interaction databases

BioGridi122327. 36 interactions.
IntActiP62068. 19 interactions.
STRINGi9606.ENSP00000407818.

Structurei

Secondary structure

1
366
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi34 – 374Combined sources
Beta strandi40 – 423Combined sources
Helixi44 – 5411Combined sources
Helixi57 – 6812Combined sources
Helixi76 – 8914Combined sources
Beta strandi91 – 977Combined sources
Helixi100 – 10910Combined sources
Helixi111 – 1133Combined sources
Beta strandi114 – 1174Combined sources
Helixi121 – 14121Combined sources
Helixi167 – 1726Combined sources
Beta strandi174 – 1829Combined sources
Turni183 – 1853Combined sources
Beta strandi188 – 20013Combined sources
Beta strandi204 – 2074Combined sources
Helixi208 – 2158Combined sources
Beta strandi219 – 2213Combined sources
Helixi223 – 2253Combined sources
Beta strandi227 – 2293Combined sources
Turni230 – 2334Combined sources
Beta strandi234 – 2363Combined sources
Beta strandi238 – 2469Combined sources
Beta strandi249 – 2557Combined sources
Beta strandi258 – 2614Combined sources
Turni262 – 2654Combined sources
Beta strandi266 – 2694Combined sources
Beta strandi278 – 2836Combined sources
Beta strandi286 – 2905Combined sources
Beta strandi293 – 31119Combined sources
Beta strandi313 – 3208Combined sources
Beta strandi323 – 3286Combined sources
Beta strandi331 – 3355Combined sources
Helixi337 – 3448Combined sources
Beta strandi354 – 36411Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
5CVMX-ray1.90A25-366[»]
5CVNX-ray3.36B25-366[»]
5CVOX-ray3.88B/E25-366[»]
ProteinModelPortaliP62068.
SMRiP62068. Positions 36-366.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini35 – 365331USPAdd
BLAST

Sequence similaritiesi

Contains 1 USP domain.Curated

Phylogenomic databases

eggNOGiKOG1864. Eukaryota.
ENOG410XQ81. LUCA.
GeneTreeiENSGT00830000128255.
HOVERGENiHBG054038.
InParanoidiP62068.
KOiK11842.
OMAiQGGSTRN.
OrthoDBiEOG7RBZ8G.
PhylomeDBiP62068.
TreeFamiTF314144.

Family and domain databases

InterProiIPR001394. Peptidase_C19_UCH.
IPR018200. USP_CS.
IPR028889. USP_dom.
[Graphical view]
PfamiPF00443. UCH. 1 hit.
[Graphical view]
PROSITEiPS00972. USP_1. 1 hit.
PS00973. USP_2. 1 hit.
PS50235. USP_3. 1 hit.
[Graphical view]

Sequences (4)i

Sequence statusi: Complete.

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P62068-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MTVRNIASIC NMGTNASALE KDIGPEQFPI NEHYFGLVNF GNTCYCNSVL
60 70 80 90 100
QALYFCRPFR ENVLAYKAQQ KKKENLLTCL ADLFHSIATQ KKKVGVIPPK
110 120 130 140 150
KFISRLRKEN DLFDNYMQQD AHEFLNYLLN TIADILQEEK KQEKQNGKLK
160 170 180 190 200
NGNMNEPAEN NKPELTWVHE IFQGTLTNET RCLNCETVSS KDEDFLDLSV
210 220 230 240 250
DVEQNTSITH CLRDFSNTET LCSEQKYYCE TCCSKQEAQK RMRVKKLPMI
260 270 280 290 300
LALHLKRFKY MEQLHRYTKL SYRVVFPLEL RLFNTSSDAV NLDRMYDLVA
310 320 330 340 350
VVVHCGSGPN RGHYITIVKS HGFWLLFDDD IVEKIDAQAI EEFYGLTSDI
360
SKNSESGYIL FYQSRE
Length:366
Mass (Da):42,442
Last modified:June 21, 2004 - v1
Checksum:i67BB113FC4081C46
GO
Isoform 2 (identifier: P62068-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-116: Missing.
     334-366: KIDAQAIEEFYGLTSDISKNSESGYILFYQSRE → VGLQIILQ

Note: No experimental confirmation available.
Show »
Length:225
Mass (Da):26,243
Checksum:i1460D49881E7AFBF
GO
Isoform 3 (identifier: P62068-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-12: MTVRNIASICNM → MNCFQ

Note: No experimental confirmation available.
Show »
Length:359
Mass (Da):41,732
Checksum:i724DEC421BEC14AC
GO
Isoform 4 (identifier: P62068-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     40-51: Missing.

Note: No experimental confirmation available.
Show »
Length:354
Mass (Da):41,112
Checksum:i0018B82362D8A874
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti177 – 1771T → A in BAH13161 (PubMed:14702039).Curated
Sequence conflicti250 – 2501I → V in BAB14133 (PubMed:14702039).Curated
Sequence conflicti265 – 2651H → R in BAB14133 (PubMed:14702039).Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti81 – 811A → V.
Corresponds to variant rs17475800 [ dbSNP | Ensembl ].
VAR_051540

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 116116Missing in isoform 2. 1 PublicationVSP_037618Add
BLAST
Alternative sequencei1 – 1212MTVRN…SICNM → MNCFQ in isoform 3. 1 PublicationVSP_037619Add
BLAST
Alternative sequencei40 – 5112Missing in isoform 4. 1 PublicationVSP_037620Add
BLAST
Alternative sequencei334 – 36633KIDAQ…YQSRE → VGLQIILQ in isoform 2. 1 PublicationVSP_037621Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
GU455414 mRNA. Translation: ADV57651.1.
AK022614 mRNA. Translation: BAB14133.1.
AK024318 mRNA. Translation: BAB14881.1.
AK296493 mRNA. Translation: BAH12373.1.
AK299883 mRNA. Translation: BAH13161.1.
AK302438 mRNA. Translation: BAH13709.1.
CH471057 Genomic DNA. Translation: EAX05435.1.
BC037574 mRNA. Translation: AAH37574.1.
CCDSiCCDS47053.1. [P62068-1]
CCDS47054.1. [P62068-3]
RefSeqiNP_001127695.1. NM_001134223.1. [P62068-3]
NP_001273696.1. NM_001286767.1. [P62068-4]
NP_001273697.1. NM_001286768.1. [P62068-2]
NP_073743.2. NM_022832.3. [P62068-1]
UniGeneiHs.7966.

Genome annotation databases

EnsembliENST00000441222; ENSP00000407818; ENSG00000109189. [P62068-1]
ENST00000508499; ENSP00000423244; ENSG00000109189. [P62068-3]
GeneIDi64854.
KEGGihsa:64854.
UCSCiuc003gzm.5. human. [P62068-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
GU455414 mRNA. Translation: ADV57651.1.
AK022614 mRNA. Translation: BAB14133.1.
AK024318 mRNA. Translation: BAB14881.1.
AK296493 mRNA. Translation: BAH12373.1.
AK299883 mRNA. Translation: BAH13161.1.
AK302438 mRNA. Translation: BAH13709.1.
CH471057 Genomic DNA. Translation: EAX05435.1.
BC037574 mRNA. Translation: AAH37574.1.
CCDSiCCDS47053.1. [P62068-1]
CCDS47054.1. [P62068-3]
RefSeqiNP_001127695.1. NM_001134223.1. [P62068-3]
NP_001273696.1. NM_001286767.1. [P62068-4]
NP_001273697.1. NM_001286768.1. [P62068-2]
NP_073743.2. NM_022832.3. [P62068-1]
UniGeneiHs.7966.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
5CVMX-ray1.90A25-366[»]
5CVNX-ray3.36B25-366[»]
5CVOX-ray3.88B/E25-366[»]
ProteinModelPortaliP62068.
SMRiP62068. Positions 36-366.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi122327. 36 interactions.
IntActiP62068. 19 interactions.
STRINGi9606.ENSP00000407818.

Protein family/group databases

MEROPSiC19.052.

Polymorphism and mutation databases

BioMutaiUSP46.
DMDMi49065850.

Proteomic databases

EPDiP62068.
MaxQBiP62068.
PaxDbiP62068.
PRIDEiP62068.

Protocols and materials databases

DNASUi64854.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000441222; ENSP00000407818; ENSG00000109189. [P62068-1]
ENST00000508499; ENSP00000423244; ENSG00000109189. [P62068-3]
GeneIDi64854.
KEGGihsa:64854.
UCSCiuc003gzm.5. human. [P62068-1]

Organism-specific databases

CTDi64854.
GeneCardsiUSP46.
HGNCiHGNC:20075. USP46.
HPAiHPA007288.
MIMi612849. gene.
neXtProtiNX_P62068.
PharmGKBiPA134922048.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1864. Eukaryota.
ENOG410XQ81. LUCA.
GeneTreeiENSGT00830000128255.
HOVERGENiHBG054038.
InParanoidiP62068.
KOiK11842.
OMAiQGGSTRN.
OrthoDBiEOG7RBZ8G.
PhylomeDBiP62068.
TreeFamiTF314144.

Miscellaneous databases

GenomeRNAii64854.
PROiP62068.
SOURCEiSearch...

Gene expression databases

BgeeiP62068.
CleanExiHS_USP46.
ExpressionAtlasiP62068. baseline and differential.
GenevisibleiP62068. HS.

Family and domain databases

InterProiIPR001394. Peptidase_C19_UCH.
IPR018200. USP_CS.
IPR028889. USP_dom.
[Graphical view]
PfamiPF00443. UCH. 1 hit.
[Graphical view]
PROSITEiPS00972. USP_1. 1 hit.
PS00973. USP_2. 1 hit.
PS50235. USP_3. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Lysine 92 amino acid residue of USP46, a gene associated with 'behavioral despair' in mice, influences the deubiquitinating enzyme activity."
    Zhang W., Tian Q.B., Li Q.K., Wang J.M., Wang C.N., Liu T., Liu D.W., Wang M.W.
    PLoS ONE 6:E26297-E26297(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), CATALYTIC ACTIVITY, ACTIVE SITE, MUTAGENESIS OF CYS-44.
  2. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
    Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
    , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
    Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2; 3 AND 4).
    Tissue: Brain, Placenta, Teratocarcinoma, Testis and Thalamus.
  3. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  4. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
    Tissue: Uterus.
  5. "Cloning and enzymatic analysis of 22 novel human ubiquitin-specific proteases."
    Quesada V., Diaz-Perales A., Gutierrez-Fernandez A., Garabaya C., Cal S., Lopez-Otin C.
    Biochem. Biophys. Res. Commun. 314:54-62(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: TISSUE SPECIFICITY, ENZYME ACTIVITY.
  6. "UAF1 is a subunit of multiple deubiquitinating enzyme complexes."
    Cohn M.A., Kee Y., Haas W., Gygi S.P., D'Andrea A.D.
    J. Biol. Chem. 284:5343-5351(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION BY MASS SPECTROMETRY, CATALYTIC ACTIVITY, FUNCTION, INTERACTION WITH WDR48.
  7. "Structural insights into WD-repeat 48 activation of ubiquitin-specific protease 46."
    Yin J., Schoeffler A.J., Wickliffe K., Newton K., Starovasnik M.A., Dueber E.C., Harris S.F.
    Structure 23:2043-2054(2015) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 25-366 IN COMPLEXES WITH WDR48 AND UBIQUITIN, ACTIVE SITE, CATALYTIC ACTIVITY, MUTAGENESIS OF CYS-44.

Entry informationi

Entry nameiUBP46_HUMAN
AccessioniPrimary (citable) accession number: P62068
Secondary accession number(s): B7Z3Y7
, B7Z675, B7Z7S3, G8ACC7, Q80V95, Q9H7U4, Q9H9T8
Entry historyi
Integrated into UniProtKB/Swiss-Prot: June 21, 2004
Last sequence update: June 21, 2004
Last modified: June 8, 2016
This is version 106 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 4
    Human chromosome 4: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Peptidase families
    Classification of peptidase families and list of entries
  7. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.