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Protein

Ubiquitin carboxyl-terminal hydrolase isozyme L1

Gene

UCHL1

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

Functioni

Ubiquitin-protein hydrolase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins. This enzyme is a thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin. Also binds to free monoubiquitin and may prevent its degradation in lysosomes. The homodimer may have ATP-independent ubiquitin ligase activity.2 Publications

Miscellaneous

Oxidation of Met-1, Met-6, Met-12, Met-124 and Met-179 to methionine sulfoxide, and oxidation of Cys-220 to cysteine sulfonic acid have been observed in brains from Alzheimer disease (AD) and Parkinson disease (PD) patients. In AD, UCHL1 was found to be associated with neurofibrillary tangles. In contrast to UCHL3, does not hydrolyze a peptide bond at the C-terminal glycine of NEDD8.

Caution

PubMed:9774100 reports the association of mutation Ile93Met with Parkinson disease. However, according to PubMed:16450370 this association is uncertain and UCHL1 is not a susceptibility gene for Parkinson disease.Curated
The oxidation forms of Met-1, Met-6, Met-12, Met-124, Met-179 and Cys-220 are subject of controversy and could be the artifactual results of sample handling.1 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).1 Publication

Kineticsi

  1. KM=122 nM for Ub-AMC3 Publications
  2. KM=1.20 µM for ubiquitin ethyl ester3 Publications
  1. Vmax=0.47 µmol/min/mg enzyme toward Ub-AMC3 Publications
  2. Vmax=25 µmol/min/mg enzyme toward ubiquitin ethyl ester3 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei1Susceptible to oxidation1 Publication1
Sitei6Susceptible to oxidation1 Publication1
Sitei12Susceptible to oxidation1 Publication1
Active sitei90Nucleophile1 Publication1
Sitei124Susceptible to oxidation1 Publication1
Active sitei161Proton donor1 Publication1
Sitei176Important for enzyme activity1 Publication1
Sitei179Susceptible to oxidation1 Publication1
Sitei220Susceptible to oxidation1 Publication1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionHydrolase, Ligase, Protease, Thiol protease
Biological processUbl conjugation pathway

Enzyme and pathway databases

BRENDAi3.4.19.12 2681
ReactomeiR-HSA-5689603 UCH proteinases
SABIO-RKiP09936
SIGNORiP09936

Protein family/group databases

MEROPSiC12.001

Names & Taxonomyi

Protein namesi
Recommended name:
Ubiquitin carboxyl-terminal hydrolase isozyme L1 (EC:3.4.19.12, EC:6.-.-.-)
Short name:
UCH-L1
Alternative name(s):
Neuron cytoplasmic protein 9.5
PGP 9.5
Short name:
PGP9.5
Ubiquitin thioesterase L1
Gene namesi
Name:UCHL1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 4

Organism-specific databases

EuPathDBiHostDB:ENSG00000154277.12
HGNCiHGNC:12513 UCHL1
MIMi191342 gene
neXtProtiNX_P09936

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Endoplasmic reticulum, Membrane

Pathology & Biotechi

Involvement in diseasei

Parkinson disease 5 (PARK5)3 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA complex neurodegenerative disorder with manifestations ranging from typical Parkinson disease to dementia with Lewy bodies. Clinical features include parkinsonian symptoms (resting tremor, rigidity, postural instability and bradykinesia), dementia, diffuse Lewy body pathology, autonomic dysfunction, hallucinations and paranoia.
See also OMIM:613643
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_01567893I → M in PARK5; impaired enzymatic hydrolase activity; has about a 50% reduction in catalytic activity compared to wild-type protein. 4 PublicationsCorresponds to variant dbSNP:rs121917767EnsemblClinVar.1
Spastic paraplegia 79, autosomal recessive (SPG79)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG79 is characterized by childhood onset blindness, cerebellar ataxia, nystagmus, dorsal column dysfunction, and spasticity with upper motor neuron dysfunction.
See also OMIM:615491
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0708757E → A in SPG79; has decreased binding to ubiquitin and significantly decreased hydrolase activity compared to wild-type. 1 PublicationCorresponds to variant dbSNP:rs397515634EnsemblClinVar.1
Natural variantiVAR_078119178R → Q in SPG79; increased hydrolase activity; decreased protein abundance. 1 PublicationCorresponds to variant dbSNP:rs768996179EnsemblClinVar.1
Natural variantiVAR_078120216A → D in SPG79; decreased protein abundance. 1 PublicationCorresponds to variant dbSNP:rs1057519600Ensembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi73Q → R: No effect on enzymatic parameters. 1 Publication1
Mutagenesisi90C → S: Abolishes enzymatic activity. 3 Publications1
Mutagenesisi97H → Q or N: 2-fold increase in affinity for ubiquitin ethyl ester, slight reduction in enzymatic activity. 1 Publication1
Mutagenesisi161H → D: 10000-fold decrease in enzymatic activity; no change in affinity for ubiquitin ethyl ester. 1 Publication1
Mutagenesisi161H → K, Q, N or Y: Abolishes enzymatic activity. 1 Publication1
Mutagenesisi176D → N: 6-fold decrease in affinity for ubiquitin ethyl ester; 97.5% decrease in enzymatic activity. 1 Publication1
Mutagenesisi204F → A: Almost complete loss of activity. 1 Publication1

Keywords - Diseasei

Disease mutation, Hereditary spastic paraplegia, Neurodegeneration, Parkinson disease, Parkinsonism

Organism-specific databases

DisGeNETi7345
GeneReviewsiUCHL1
MalaCardsiUCHL1
MIMi613643 phenotype
615491 phenotype
OpenTargetsiENSG00000154277
Orphaneti352654 Early-onset progressive neurodegeneration - blindness - ataxia - spasticity
2828 Young adult-onset Parkinsonism
PharmGKBiPA37160

Chemistry databases

ChEMBLiCHEMBL6159
GuidetoPHARMACOLOGYi2426

Polymorphism and mutation databases

BioMutaiUCHL1
DMDMi136681

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002110551 – 220Ubiquitin carboxyl-terminal hydrolase isozyme L1Add BLAST220
PropeptideiPRO_0000414311221 – 223Removed in mature formCurated3

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei125PhosphoserineBy similarity1
Lipidationi220S-farnesyl cysteine1 Publication1

Post-translational modificationi

O-glycosylated.By similarity

Keywords - PTMi

Glycoprotein, Lipoprotein, Oxidation, Phosphoprotein, Prenylation

Proteomic databases

EPDiP09936
PaxDbiP09936
PeptideAtlasiP09936
PRIDEiP09936
ProteomicsDBi52282
TopDownProteomicsiP09936

2D gel databases

DOSAC-COBS-2DPAGEiP09936
UCD-2DPAGEiP09936

PTM databases

iPTMnetiP09936
PhosphoSitePlusiP09936
SwissPalmiP09936

Expressioni

Tissue specificityi

Found in neuronal cell bodies and processes throughout the neocortex (at protein level). Expressed in neurons and cells of the diffuse neuroendocrine system and their tumors. Weakly expressed in ovary. Down-regulated in brains from Parkinson disease and Alzheimer disease patients.2 Publications

Gene expression databases

BgeeiENSG00000154277 Expressed in 199 organ(s), highest expression level in anterior cingulate cortex
CleanExiHS_UCHL1
ExpressionAtlasiP09936 baseline and differential
GenevisibleiP09936 HS

Organism-specific databases

HPAiCAB002580
CAB079024
HPA005993

Interactioni

Subunit structurei

Monomer. Homodimer. Interacts with SNCA (By similarity). Interacts with COPS5.By similarity3 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi113192, 58 interactors
DIPiDIP-36620N
IntActiP09936, 29 interactors
MINTiP09936
STRINGi9606.ENSP00000284440

Chemistry databases

BindingDBiP09936

Structurei

Secondary structure

1223
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliP09936
SMRiP09936
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP09936

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni5 – 10Interaction with ubiquitin1 Publication6
Regioni211 – 216Interaction with ubiquitin1 Publication6

Sequence similaritiesi

Belongs to the peptidase C12 family.Curated

Phylogenomic databases

eggNOGiKOG1415 Eukaryota
ENOG4111HNA LUCA
GeneTreeiENSGT00510000046640
HOGENOMiHOG000182400
HOVERGENiHBG075483
InParanoidiP09936
KOiK05611
PhylomeDBiP09936
TreeFamiTF316166

Family and domain databases

Gene3Di3.40.532.10, 1 hit
InterProiView protein in InterPro
IPR038765 Papain_like_cys_pep_sf
IPR001578 Peptidase_C12_UCH
IPR036959 Peptidase_C12_UCH_sf
IPR030297 UCHL1
PANTHERiPTHR10589 PTHR10589, 1 hit
PTHR10589:SF19 PTHR10589:SF19, 1 hit
PfamiView protein in Pfam
PF01088 Peptidase_C12, 1 hit
PRINTSiPR00707 UBCTHYDRLASE
SUPFAMiSSF54001 SSF54001, 1 hit
PROSITEiView protein in PROSITE
PS00140 UCH_1, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry has 1 described isoform and 5 potential isoforms that are computationally mapped.Show allAlign All

P09936-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MQLKPMEINP EMLNKVLSRL GVAGQWRFVD VLGLEEESLG SVPAPACALL
60 70 80 90 100
LLFPLTAQHE NFRKKQIEEL KGQEVSPKVY FMKQTIGNSC GTIGLIHAVA
110 120 130 140 150
NNQDKLGFED GSVLKQFLSE TEKMSPEDRA KCFEKNEAIQ AAHDAVAQEG
160 170 180 190 200
QCRVDDKVNF HFILFNNVDG HLYELDGRMP FPVNHGASSE DTLLKDAAKV
210 220
CREFTEREQG EVRFSAVALC KAA
Length:223
Mass (Da):24,824
Last modified:November 1, 1990 - v2
Checksum:iC9E972AC4DA5DA8A
GO

Computationally mapped potential isoform sequencesi

There are 5 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
D6R956D6R956_HUMAN
Ubiquitin carboxyl-terminal hydrola...
UCHL1
241Annotation score:
D6RE83D6RE83_HUMAN
Ubiquitin carboxyl-terminal hydrola...
UCHL1
207Annotation score:
D6R974D6R974_HUMAN
Ubiquitin carboxyl-terminal hydrola...
UCHL1
156Annotation score:
D6RF53D6RF53_HUMAN
Ubiquitin carboxyl-terminal hydrola...
UCHL1
58Annotation score:
D6RJD9D6RJD9_HUMAN
Ubiquitin carboxyl-terminal hydrola...
UCHL1
69Annotation score:

Sequence cautioni

The sequence CAA28443 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0708757E → A in SPG79; has decreased binding to ubiquitin and significantly decreased hydrolase activity compared to wild-type. 1 PublicationCorresponds to variant dbSNP:rs397515634EnsemblClinVar.1
Natural variantiVAR_01567718S → Y Polymorphism; may be associated with reduced risk for sporadic Parkinson disease; it confers protection from oxidative stress when expressed at physiological levels in neuroblastoma cells and primary cortical neurons; loss of dimerization ability; impaired ligase activity. 8 PublicationsCorresponds to variant dbSNP:rs5030732EnsemblClinVar.1
Natural variantiVAR_01567893I → M in PARK5; impaired enzymatic hydrolase activity; has about a 50% reduction in catalytic activity compared to wild-type protein. 4 PublicationsCorresponds to variant dbSNP:rs121917767EnsemblClinVar.1
Natural variantiVAR_078119178R → Q in SPG79; increased hydrolase activity; decreased protein abundance. 1 PublicationCorresponds to variant dbSNP:rs768996179EnsemblClinVar.1
Natural variantiVAR_078120216A → D in SPG79; decreased protein abundance. 1 PublicationCorresponds to variant dbSNP:rs1057519600Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AC095043 Genomic DNA Translation: AAY40923.1
CH471069 Genomic DNA Translation: EAW92983.1
BC000332 mRNA Translation: AAH00332.1
BC005117 mRNA Translation: AAH05117.1
BC006305 mRNA Translation: AAH06305.1
X17377 Genomic DNA Translation: CAA35249.1
X04741 mRNA Translation: CAA28443.1 Different initiation.
AH007277 Genomic DNA Translation: AAD09172.1
CCDSiCCDS3462.1
PIRiA25856
RefSeqiNP_004172.2, NM_004181.4
UniGeneiHs.518731

Genome annotation databases

EnsembliENST00000284440; ENSP00000284440; ENSG00000154277
ENST00000503431; ENSP00000422542; ENSG00000154277
GeneIDi7345
KEGGihsa:7345

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Cross-referencesi

Web resourcesi

Wikipedia

Ubiquitin carboxy-terminal hydrolase L1 entry

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AC095043 Genomic DNA Translation: AAY40923.1
CH471069 Genomic DNA Translation: EAW92983.1
BC000332 mRNA Translation: AAH00332.1
BC005117 mRNA Translation: AAH05117.1
BC006305 mRNA Translation: AAH06305.1
X17377 Genomic DNA Translation: CAA35249.1
X04741 mRNA Translation: CAA28443.1 Different initiation.
AH007277 Genomic DNA Translation: AAD09172.1
CCDSiCCDS3462.1
PIRiA25856
RefSeqiNP_004172.2, NM_004181.4
UniGeneiHs.518731

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2ETLX-ray2.40A/B1-223[»]
2LENNMR-A1-223[»]
3IFWX-ray2.40A1-223[»]
3IRTX-ray2.80A/B1-223[»]
3KVFX-ray2.80A1-223[»]
3KW5X-ray2.83A1-223[»]
4DM9X-ray2.35A/B1-223[»]
4JKJX-ray2.15A/B1-223[»]
ProteinModelPortaliP09936
SMRiP09936
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi113192, 58 interactors
DIPiDIP-36620N
IntActiP09936, 29 interactors
MINTiP09936
STRINGi9606.ENSP00000284440

Chemistry databases

BindingDBiP09936
ChEMBLiCHEMBL6159
GuidetoPHARMACOLOGYi2426

Protein family/group databases

MEROPSiC12.001

PTM databases

iPTMnetiP09936
PhosphoSitePlusiP09936
SwissPalmiP09936

Polymorphism and mutation databases

BioMutaiUCHL1
DMDMi136681

2D gel databases

DOSAC-COBS-2DPAGEiP09936
UCD-2DPAGEiP09936

Proteomic databases

EPDiP09936
PaxDbiP09936
PeptideAtlasiP09936
PRIDEiP09936
ProteomicsDBi52282
TopDownProteomicsiP09936

Protocols and materials databases

DNASUi7345
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000284440; ENSP00000284440; ENSG00000154277
ENST00000503431; ENSP00000422542; ENSG00000154277
GeneIDi7345
KEGGihsa:7345

Organism-specific databases

CTDi7345
DisGeNETi7345
EuPathDBiHostDB:ENSG00000154277.12
GeneCardsiUCHL1
GeneReviewsiUCHL1
HGNCiHGNC:12513 UCHL1
HPAiCAB002580
CAB079024
HPA005993
MalaCardsiUCHL1
MIMi191342 gene
613643 phenotype
615491 phenotype
neXtProtiNX_P09936
OpenTargetsiENSG00000154277
Orphaneti352654 Early-onset progressive neurodegeneration - blindness - ataxia - spasticity
2828 Young adult-onset Parkinsonism
PharmGKBiPA37160
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1415 Eukaryota
ENOG4111HNA LUCA
GeneTreeiENSGT00510000046640
HOGENOMiHOG000182400
HOVERGENiHBG075483
InParanoidiP09936
KOiK05611
PhylomeDBiP09936
TreeFamiTF316166

Enzyme and pathway databases

BRENDAi3.4.19.12 2681
ReactomeiR-HSA-5689603 UCH proteinases
SABIO-RKiP09936
SIGNORiP09936

Miscellaneous databases

ChiTaRSiUCHL1 human
EvolutionaryTraceiP09936
GeneWikiiUbiquitin_carboxy-terminal_hydrolase_L1
GenomeRNAii7345
PROiPR:P09936
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000154277 Expressed in 199 organ(s), highest expression level in anterior cingulate cortex
CleanExiHS_UCHL1
ExpressionAtlasiP09936 baseline and differential
GenevisibleiP09936 HS

Family and domain databases

Gene3Di3.40.532.10, 1 hit
InterProiView protein in InterPro
IPR038765 Papain_like_cys_pep_sf
IPR001578 Peptidase_C12_UCH
IPR036959 Peptidase_C12_UCH_sf
IPR030297 UCHL1
PANTHERiPTHR10589 PTHR10589, 1 hit
PTHR10589:SF19 PTHR10589:SF19, 1 hit
PfamiView protein in Pfam
PF01088 Peptidase_C12, 1 hit
PRINTSiPR00707 UBCTHYDRLASE
SUPFAMiSSF54001 SSF54001, 1 hit
PROSITEiView protein in PROSITE
PS00140 UCH_1, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiUCHL1_HUMAN
AccessioniPrimary (citable) accession number: P09936
Secondary accession number(s): Q4W5K6, Q71UM0
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 1, 1989
Last sequence update: November 1, 1990
Last modified: September 12, 2018
This is version 207 of the entry and version 2 of the sequence. See 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, Direct protein sequencing, Reference proteome

Documents

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

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