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Protein

Ubiquitin carboxyl-terminal hydrolase isozyme L1

Gene

UCHL1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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.

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

  • alpha-2A adrenergic receptor binding Source: BHF-UCL
  • cysteine-type endopeptidase activity Source: UniProtKB
  • ligase activity Source: UniProtKB-KW
  • omega peptidase activity Source: UniProtKB
  • thiol-dependent ubiquitin-specific protease activity Source: GO_Central
  • thiol-dependent ubiquitinyl hydrolase activity Source: Reactome
  • ubiquitin binding Source: UniProtKB
  • ubiquitin protein ligase binding Source: ParkinsonsUK-UCL

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.

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:rs121917767Ensembl.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:rs397515634Ensembl.1
Natural variantiVAR_078119178R → Q in SPG79; increased hydrolase activity; decreased protein abundance. 1 PublicationCorresponds to variant dbSNP:rs768996179Ensembl.1
Natural variantiVAR_078120216A → D in SPG79; decreased protein abundance. 1 Publication1

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.
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.
CleanExiHS_UCHL1.
ExpressionAtlasiP09936. baseline and differential.
GenevisibleiP09936. HS.

Organism-specific databases

HPAiCAB002580.
HPA005993.

Interactioni

Subunit structurei

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

Binary interactionsi

Show more details

GO - Molecular functioni

  • alpha-2A adrenergic receptor binding Source: BHF-UCL
  • ubiquitin binding Source: UniProtKB
  • ubiquitin protein ligase binding Source: ParkinsonsUK-UCL

Protein-protein interaction databases

BioGridi113192. 54 interactors.
DIPiDIP-36620N.
IntActiP09936. 32 interactors.
MINTiMINT-1378022.
STRINGi9606.ENSP00000284440.

Chemistry databases

BindingDBiP09936.

Structurei

Secondary structure

1223
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi10 – 19Combined sources10
Beta strandi22 – 30Combined sources9
Helixi36 – 38Combined sources3
Beta strandi39 – 42Combined sources4
Beta strandi46 – 54Combined sources9
Helixi57 – 70Combined sources14
Turni71 – 74Combined sources4
Beta strandi86 – 88Combined sources3
Helixi90 – 100Combined sources11
Turni101 – 105Combined sources5
Helixi113 – 120Combined sources8
Turni121 – 123Combined sources3
Helixi126 – 134Combined sources9
Helixi137 – 147Combined sources11
Beta strandi160 – 168Combined sources9
Beta strandi171 – 175Combined sources5
Beta strandi179 – 181Combined sources3
Beta strandi183 – 187Combined sources5
Helixi190 – 192Combined sources3
Helixi193 – 207Combined sources15
Helixi211 – 213Combined sources3
Beta strandi215 – 221Combined sources7

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...

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
IPR001578. Peptidase_C12_UCH.
IPR030297. UCHL1.
PANTHERiPTHR10589. PTHR10589. 1 hit.
PTHR10589:SF33. PTHR10589:SF33. 1 hit.
PfamiView protein in Pfam
PF01088. Peptidase_C12. 1 hit.
PRINTSiPR00707. UBCTHYDRLASE.
PROSITEiView protein in PROSITE
PS00140. UCH_1. 1 hit.

Sequencei

Sequence statusi: Complete.

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

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

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:rs397515634Ensembl.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:rs5030732Ensembl.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:rs121917767Ensembl.1
Natural variantiVAR_078119178R → Q in SPG79; increased hydrolase activity; decreased protein abundance. 1 PublicationCorresponds to variant dbSNP:rs768996179Ensembl.1
Natural variantiVAR_078120216A → D in SPG79; decreased protein abundance. 1 Publication1

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

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 27, 2017
This is version 198 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

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

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, 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