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Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCH-L1) (EC 3.4.19.12) (EC 6.-.-.-) (Neuron cytoplasmic protein 9.5) (PGP 9.5) (PGP9.5) (Ubiquitin thioesterase L1)

 UCHL1_HUMAN             Reviewed;         223 AA.
P09936; Q4W5K6; Q71UM0;
01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
01-NOV-1990, sequence version 2.
27-SEP-2017, entry version 198.
RecName: Full=Ubiquitin carboxyl-terminal hydrolase isozyme L1;
Short=UCH-L1;
EC=3.4.19.12;
EC=6.-.-.-;
AltName: Full=Neuron cytoplasmic protein 9.5;
AltName: Full=PGP 9.5;
Short=PGP9.5;
AltName: Full=Ubiquitin thioesterase L1;
Flags: Precursor;
Name=UCHL1;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=15815621; DOI=10.1038/nature03466;
Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
Waterston R.H., Wilson R.K.;
"Generation and annotation of the DNA sequences of human chromosomes 2
and 4.";
Nature 434:724-731(2005).
[2]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
Venter J.C.;
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
[3]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
TISSUE=Lung, and Muscle;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[4]
NUCLEOTIDE SEQUENCE [MRNA] OF 1-15.
PubMed=2163617; DOI=10.1042/bj2680521;
Day I.N.M., Hinks L.J., Thompson R.J.;
"The structure of the human gene encoding protein gene product 9.5
(PGP9.5), a neuron-specific ubiquitin C-terminal hydrolase.";
Biochem. J. 268:521-524(1990).
[5]
PROTEIN SEQUENCE OF 1-15 AND 214-221, SUSCEPTIBILITY TO OXIDATION,
IDENTIFICATION BY MASS SPECTROMETRY, AND TISSUE SPECIFICITY.
PubMed=14722078; DOI=10.1074/jbc.M314124200;
Choi J., Levey A.I., Weintraub S.T., Rees H.D., Gearing M.,
Chin L.-S., Li L.;
"Oxidative modifications and down-regulation of ubiquitin carboxyl-
terminal hydrolase L1 associated with idiopathic Parkinson's and
Alzheimer's diseases.";
J. Biol. Chem. 279:13256-13264(2004).
[6]
PROTEIN SEQUENCE OF 1-15; 20-27; 66-78; 84-129; 136-195 AND 214-221,
AND IDENTIFICATION BY MASS SPECTROMETRY.
TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
Lubec G., Afjehi-Sadat L., Chen W.-Q., Sun Y.;
Submitted (DEC-2008) to UniProtKB.
[7]
NUCLEOTIDE SEQUENCE [MRNA] OF 7-223, AND PARTIAL PROTEIN SEQUENCE.
PubMed=2947814; DOI=10.1016/0014-5793(87)81327-3;
Day I.N.M., Thompson R.J.;
"Molecular cloning of cDNA coding for human PGP 9.5 protein. A novel
cytoplasmic marker for neurones and neuroendocrine cells.";
FEBS Lett. 210:157-160(1987).
[8]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 16-223, VARIANT PARK5 MET-93,
CHARACTERIZATION OF VARIANT PARK5 MET-93, AND BIOPHYSICOCHEMICAL
PROPERTIES.
PubMed=9774100; DOI=10.1038/26652;
Leroy E., Boyer R., Auburger G., Leube B., Ulm G., Mezey E., Harta G.,
Brownstein M.J., Jonnalagada S., Chernova T., Dehejia A., Lavedan C.,
Gasser T., Steinbach P.J., Wilkinson K.D., Polymeropoulos M.H.;
"The ubiquitin pathway in Parkinson's disease.";
Nature 395:451-452(1998).
[9]
PROTEIN SEQUENCE OF 20-25; 79-81; 106-121 AND 134-151.
PubMed=1849484; DOI=10.1016/0014-5793(91)80300-R;
Honore B., Rasmussen H.H., Vandekerckhove J., Celis J.E.;
"Neuronal protein gene product 9.5 (IEF SSP 6104) is expressed in
cultured human MRC-5 fibroblasts of normal origin and is strongly
down-regulated in their SV40 transformed counterparts.";
FEBS Lett. 280:235-240(1991).
[10]
PROTEIN SEQUENCE OF 20-25; 79-91; 106-123 AND 136-151.
PubMed=1286667; DOI=10.1002/elps.11501301199;
Rasmussen H.H., van Damme J., Puype M., Gesser B., Celis J.E.,
Vandekerckhove J.;
"Microsequences of 145 proteins recorded in the two-dimensional gel
protein database of normal human epidermal keratinocytes.";
Electrophoresis 13:960-969(1992).
[11]
ACTIVE SITE, MUTAGENESIS OF GLN-73; CYS-90; HIS-97; HIS-161 AND
ASP-176, AND BIOPHYSICOCHEMICAL PROPERTIES.
PubMed=8639624; DOI=10.1021/bi960099f;
Larsen C.N., Price J.S., Wilkinson K.D.;
"Substrate binding and catalysis by ubiquitin C-terminal hydrolases:
identification of two active site residues.";
Biochemistry 35:6735-6744(1996).
[12]
FUNCTION, AND TISSUE SPECIFICITY.
PubMed=9790970; DOI=10.1006/bbrc.1998.9532;
Wada H., Kito K., Caskey L.S., Yeh E.T.H., Kamitani T.;
"Cleavage of the C-terminus of NEDD8 by UCH-L3.";
Biochem. Biophys. Res. Commun. 251:688-692(1998).
[13]
FUNCTION, CHARACTERIZATION OF VARIANT PARK5 MET-93, AND
CHARACTERIZATION OF VARIANT TYR-18.
PubMed=12408865; DOI=10.1016/S0092-8674(02)01012-7;
Liu Y., Fallon L., Lashuel H.A., Liu Z., Lansbury P.T. Jr.;
"The UCH-L1 gene encodes two opposing enzymatic activities that affect
alpha-synuclein degradation and Parkinson's disease susceptibility.";
Cell 111:209-218(2002).
[14]
INTERACTION WITH COPS5.
PubMed=12082530; DOI=10.1038/sj.onc.1205390;
Caballero O.L., Resto V., Patturajan M., Meerzaman D., Guo M.Z.,
Engles J., Yochem R., Ratovitski E., Sidransky D., Jen J.;
"Interaction and colocalization of PGP9.5 with JAB1 and p27(Kip1).";
Oncogene 21:3003-3010(2002).
[15]
ACTIVE SITE.
PubMed=16475834; DOI=10.1021/bi052135t;
Case A., Stein R.L.;
"Mechanistic studies of ubiquitin C-terminal hydrolase L1.";
Biochemistry 45:2443-2452(2006).
[16]
SUBCELLULAR LOCATION, AND ISOPRENYLATION AT CYS-220.
PubMed=19261853; DOI=10.1073/pnas.0806474106;
Liu Z., Meray R.K., Grammatopoulos T.N., Fredenburg R.A.,
Cookson M.R., Liu Y., Logan T., Lansbury P.T. Jr.;
"Membrane-associated farnesylated UCH-L1 promotes alpha-synuclein
neurotoxicity and is a therapeutic target for Parkinson's disease.";
Proc. Natl. Acad. Sci. U.S.A. 106:4635-4640(2009).
[17]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=19608861; DOI=10.1126/science.1175371;
Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
Walther T.C., Olsen J.V., Mann M.;
"Lysine acetylation targets protein complexes and co-regulates major
cellular functions.";
Science 325:834-840(2009).
[18]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=21269460; DOI=10.1186/1752-0509-5-17;
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
"Initial characterization of the human central proteome.";
BMC Syst. Biol. 5:17-17(2011).
[19]
X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS), AND SUBUNIT.
PubMed=16537382; DOI=10.1073/pnas.0510403103;
Das C., Hoang Q.Q., Kreinbring C.A., Luchansky S.J., Meray R.K.,
Ray S.S., Lansbury P.T., Ringe D., Petsko G.A.;
"Structural basis for conformational plasticity of the Parkinson's
disease-associated ubiquitin hydrolase UCH-L1.";
Proc. Natl. Acad. Sci. U.S.A. 103:4675-4680(2006).
[20]
X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF VARIANTS TYR-18 AND MET-93 IN
COMPLEX WITH UBIQUITIN, CATALYTIC ACTIVITY, ACTIVE SITE, AND
MUTAGENESIS OF CYS-90 AND PHE-204.
PubMed=20439756; DOI=10.1073/pnas.0910870107;
Boudreaux D.A., Maiti T.K., Davies C.W., Das C.;
"Ubiquitin vinyl methyl ester binding orients the misaligned active
site of the ubiquitin hydrolase UCHL1 into productive conformation.";
Proc. Natl. Acad. Sci. U.S.A. 107:9117-9122(2010).
[21]
CHARACTERIZATION OF VARIANT PARK5 MET-93, CHARACTERIZATION OF VARIANT
TYR-18, MUTAGENESIS OF CYS-90, AND BIOPHYSICOCHEMICAL PROPERTIES.
PubMed=12705903; DOI=10.1016/S0006-291X(03)00555-2;
Nishikawa K., Li H., Kawamura R., Osaka H., Wang Y.-L., Hara Y.,
Hirokawa T., Manago Y., Amano T., Noda M., Aoki S., Wada K.;
"Alterations of structure and hydrolase activity of parkinsonism-
associated human ubiquitin carboxyl-terminal hydrolase L1 variants.";
Biochem. Biophys. Res. Commun. 304:176-183(2003).
[22]
VARIANT MET-93.
PubMed=10454131; DOI=10.1016/S0304-3940(99)00465-6;
Harhangi B.S., Farrer M.J., Lincoln S., Bonifati V., Meco G.,
De Michele G., Brice A., Durr A., Martinez M., Gasser T., Bereznai B.,
Vaughan J.R., Wood N.W., Hardy J., Oostra B.A., Breteler M.M.;
"The Ile93Met mutation in the ubiquitin carboxy-terminal-hydrolase-L1
gene is not observed in European cases with familial Parkinson's
disease.";
Neurosci. Lett. 270:1-4(1999).
[23]
VARIANT TYR-18.
PubMed=10203348; DOI=10.1097/00001756-199902050-00040;
Lincoln S., Vaughan J., Wood N., Baker M., Adamson J., Gwinn-Hardy K.,
Lynch T., Hardy J., Farrer M.;
"Low frequency of pathogenic mutations in the ubiquitin carboxy-
terminal hydrolase gene in familial Parkinson's disease.";
NeuroReport 10:427-429(1999).
[24]
VARIANT TYR-18.
PubMed=11027850; DOI=10.1016/S0304-3940(00)01510-X;
Mellick G.D., Silburn P.A.;
"The ubiquitin carboxy-terminal hydrolase-L1 gene S18Y polymorphism
does not confer protection against idiopathic Parkinson's disease.";
Neurosci. Lett. 293:127-130(2000).
[25]
VARIANT TYR-18.
PubMed=15048890; DOI=10.1002/ana.20017;
UCHL1 global genetics consortium;
Maraganore D.M., Lesnick T.G., Elbaz A., Chartier-Harlin M.-C.,
Gasser T., Krueger R., Hattori N., Mellick G.D., Quattrone A.,
Satoh J., Toda T., Wang J., Ioannidis J.P.A., de Andrade M.,
Rocca W.A.;
"UCHL1 is a Parkinson's disease susceptibility gene.";
Ann. Neurol. 55:512-521(2004).
[26]
ERRATUM.
UCHL1 global genetics consortium;
Maraganore D.M., Lesnick T.G., Elbaz A., Chartier-Harlin M.-C.,
Gasser T., Krueger R., Hattori N., Mellick G.D., Quattrone A.,
Satoh J., Toda T., Wang J., Ioannidis J.P.A., de Andrade M.,
Rocca W.A.;
Ann. Neurol. 55:899-899(2004).
[27]
VARIANT TYR-18, AND LACK OF ASSOCIATION OF VARIANT TYR-18 WITH
PARKINSON DISEASE.
PubMed=16450370; DOI=10.1002/ana.20757;
Healy D.G., Abou-Sleiman P.M., Casas J.P., Ahmadi K.R., Lynch T.,
Gandhi S., Muqit M.M., Foltynie T., Barker R., Bhatia K.P.,
Quinn N.P., Lees A.J., Gibson J.M., Holton J.L., Revesz T.,
Goldstein D.B., Wood N.W.;
"UCHL-1 is not a Parkinson's disease susceptibility gene.";
Ann. Neurol. 59:627-633(2006).
[28]
CHARACTERIZATION OF VARIANT TYR-18, AND ANTIOXIDANT FUNCTION IN
NEURONAL CELLS.
PubMed=18411255; DOI=10.1093/hmg/ddn115;
Kyratzi E., Pavlaki M., Stefanis L.;
"The S18Y polymorphic variant of UCH-L1 confers an antioxidant
function to neuronal cells.";
Hum. Mol. Genet. 17:2160-2171(2008).
[29]
VARIANT TYR-18.
PubMed=21268678; DOI=10.3109/13816810.2010.544360;
Rudolph T., Sjolander A., Palmer M.S., Minthon L., Wallin A.,
Andreasen N., Tasa G., Juronen E., Blennow K., Zetterberg H.,
Zetterberg M.;
"Ubiquitin carboxyl-terminal esterase L1 (UCHL1) S18Y polymorphism in
patients with cataracts.";
Ophthalmic Genet. 32:75-79(2011).
[30]
VARIANT SPG79 ALA-7, AND CHARACTERIZATION OF VARIANT SPG79 ALA-7.
PubMed=23359680; DOI=10.1073/pnas.1222732110;
Bilguvar K., Tyagi N.K., Ozkara C., Tuysuz B., Bakircioglu M.,
Choi M., Delil S., Caglayan A.O., Baranoski J.F., Erturk O.,
Yalcinkaya C., Karacorlu M., Dincer A., Johnson M.H., Mane S.,
Chandra S.S., Louvi A., Boggon T.J., Lifton R.P., Horwich A.L.,
Gunel M.;
"Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1
leads to early-onset progressive neurodegeneration.";
Proc. Natl. Acad. Sci. U.S.A. 110:3489-3494(2013).
[31]
VARIANTS SPG79 GLN-178 AND ASP-216, AND CHARACTERIZATION OF VARIANTS
SPG79 GLN-178 AND ASP-216.
PubMed=28007905; DOI=10.1093/hmg/ddw391;
Rydning S.L., Backe P.H., Sousa M.M., Iqbal Z., Oeye A.M., Sheng Y.,
Yang M., Lin X., Slupphaug G., Nordenmark T.H., Vigeland M.D.,
Bjoeraas M., Tallaksen C.M., Selmer K.K.;
"Novel UCHL1 mutations reveal new insights into ubiquitin
processing.";
Hum. Mol. Genet. 26:1031-1040(2017).
-!- FUNCTION: 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.
{ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:9790970}.
-!- CATALYTIC ACTIVITY: 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).
{ECO:0000269|PubMed:20439756}.
-!- BIOPHYSICOCHEMICAL PROPERTIES:
Kinetic parameters:
KM=122 nM for Ub-AMC {ECO:0000269|PubMed:12705903,
ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100};
KM=1.20 uM for ubiquitin ethyl ester
{ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:8639624,
ECO:0000269|PubMed:9774100};
Vmax=0.47 umol/min/mg enzyme toward Ub-AMC
{ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:8639624,
ECO:0000269|PubMed:9774100};
Vmax=25 umol/min/mg enzyme toward ubiquitin ethyl ester
{ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:8639624,
ECO:0000269|PubMed:9774100};
-!- SUBUNIT: Monomer. Homodimer. Interacts with SNCA (By similarity).
Interacts with COPS5. {ECO:0000250, ECO:0000269|PubMed:12082530,
ECO:0000269|PubMed:16537382, ECO:0000269|PubMed:20439756}.
-!- INTERACTION:
Q92905:COPS5; NbExp=3; IntAct=EBI-714860, EBI-594661;
P00533:EGFR; NbExp=2; IntAct=EBI-714860, EBI-297353;
Q9NYB0:TERF2IP; NbExp=2; IntAct=EBI-714860, EBI-750109;
-!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19261853}.
Endoplasmic reticulum membrane {ECO:0000269|PubMed:19261853};
Lipid-anchor {ECO:0000269|PubMed:19261853}. Note=About 30% of
total UCHL1 is associated with membranes in brain.
-!- TISSUE SPECIFICITY: 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.
{ECO:0000269|PubMed:14722078, ECO:0000269|PubMed:9790970}.
-!- PTM: O-glycosylated. {ECO:0000250}.
-!- DISEASE: Parkinson disease 5 (PARK5) [MIM:613643]: A 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. {ECO:0000269|PubMed:12408865,
ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:9774100}. Note=The
disease is caused by mutations affecting the gene represented in
this entry.
-!- DISEASE: Spastic paraplegia 79, autosomal recessive (SPG79)
[MIM:615491]: A 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.
{ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:28007905}.
Note=The disease is caused by mutations affecting the gene
represented in this entry.
-!- 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.
-!- SIMILARITY: Belongs to the peptidase C12 family. {ECO:0000305}.
-!- 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. {ECO:0000305}.
-!- CAUTION: 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.
{ECO:0000305|PubMed:14722078}.
-!- SEQUENCE CAUTION:
Sequence=CAA28443.1; Type=Erroneous initiation; Note=Translation N-terminally extended.; Evidence={ECO:0000305};
-!- WEB RESOURCE: Name=Wikipedia; Note=Ubiquitin carboxy-terminal
hydrolase L1 entry;
URL="https://en.wikipedia.org/wiki/Ubiquitin_carboxy-terminal_hydrolase_L1";
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EMBL; AC095043; AAY40923.1; -; Genomic_DNA.
EMBL; CH471069; EAW92983.1; -; Genomic_DNA.
EMBL; BC000332; AAH00332.1; -; mRNA.
EMBL; BC005117; AAH05117.1; -; mRNA.
EMBL; BC006305; AAH06305.1; -; mRNA.
EMBL; X17377; CAA35249.1; -; Genomic_DNA.
EMBL; X04741; CAA28443.1; ALT_INIT; mRNA.
EMBL; AH007277; AAD09172.1; -; Genomic_DNA.
CCDS; CCDS3462.1; -.
PIR; A25856; A25856.
RefSeq; NP_004172.2; NM_004181.4.
UniGene; Hs.518731; -.
PDB; 2ETL; X-ray; 2.40 A; A/B=1-223.
PDB; 2LEN; NMR; -; A=1-223.
PDB; 3IFW; X-ray; 2.40 A; A=1-223.
PDB; 3IRT; X-ray; 2.80 A; A/B=1-223.
PDB; 3KVF; X-ray; 2.80 A; A=1-223.
PDB; 3KW5; X-ray; 2.83 A; A=1-223.
PDB; 4DM9; X-ray; 2.35 A; A/B=1-223.
PDB; 4JKJ; X-ray; 2.15 A; A/B=1-223.
PDBsum; 2ETL; -.
PDBsum; 2LEN; -.
PDBsum; 3IFW; -.
PDBsum; 3IRT; -.
PDBsum; 3KVF; -.
PDBsum; 3KW5; -.
PDBsum; 4DM9; -.
PDBsum; 4JKJ; -.
ProteinModelPortal; P09936; -.
SMR; P09936; -.
BioGrid; 113192; 54.
DIP; DIP-36620N; -.
IntAct; P09936; 32.
MINT; MINT-1378022; -.
STRING; 9606.ENSP00000284440; -.
BindingDB; P09936; -.
ChEMBL; CHEMBL6159; -.
GuidetoPHARMACOLOGY; 2426; -.
MEROPS; C12.001; -.
iPTMnet; P09936; -.
PhosphoSitePlus; P09936; -.
SwissPalm; P09936; -.
BioMuta; UCHL1; -.
DMDM; 136681; -.
DOSAC-COBS-2DPAGE; P09936; -.
UCD-2DPAGE; P09936; -.
EPD; P09936; -.
PaxDb; P09936; -.
PeptideAtlas; P09936; -.
PRIDE; P09936; -.
TopDownProteomics; P09936; -.
DNASU; 7345; -.
Ensembl; ENST00000284440; ENSP00000284440; ENSG00000154277.
Ensembl; ENST00000503431; ENSP00000422542; ENSG00000154277.
GeneID; 7345; -.
KEGG; hsa:7345; -.
CTD; 7345; -.
DisGeNET; 7345; -.
EuPathDB; HostDB:ENSG00000154277.12; -.
GeneCards; UCHL1; -.
GeneReviews; UCHL1; -.
HGNC; HGNC:12513; UCHL1.
HPA; CAB002580; -.
HPA; HPA005993; -.
MalaCards; UCHL1; -.
MIM; 191342; gene.
MIM; 613643; phenotype.
MIM; 615491; phenotype.
neXtProt; NX_P09936; -.
OpenTargets; ENSG00000154277; -.
Orphanet; 352654; Early-onset progressive neurodegeneration - blindness - ataxia - spasticity.
Orphanet; 2828; Young adult-onset Parkinsonism.
PharmGKB; PA37160; -.
eggNOG; KOG1415; Eukaryota.
eggNOG; ENOG4111HNA; LUCA.
GeneTree; ENSGT00510000046640; -.
HOGENOM; HOG000182400; -.
HOVERGEN; HBG075483; -.
InParanoid; P09936; -.
KO; K05611; -.
PhylomeDB; P09936; -.
TreeFam; TF316166; -.
BRENDA; 3.4.19.12; 2681.
Reactome; R-HSA-5689603; UCH proteinases.
SABIO-RK; P09936; -.
SIGNOR; P09936; -.
ChiTaRS; UCHL1; human.
EvolutionaryTrace; P09936; -.
GeneWiki; Ubiquitin_carboxy-terminal_hydrolase_L1; -.
GenomeRNAi; 7345; -.
PRO; PR:P09936; -.
Proteomes; UP000005640; Chromosome 4.
Bgee; ENSG00000154277; -.
CleanEx; HS_UCHL1; -.
ExpressionAtlas; P09936; baseline and differential.
Genevisible; P09936; HS.
GO; GO:1904115; C:axon cytoplasm; IEA:GOC.
GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL.
GO; GO:0005829; C:cytosol; IDA:HPA.
GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
GO; GO:0070062; C:extracellular exosome; IDA:UniProtKB.
GO; GO:0043209; C:myelin sheath; IEA:Ensembl.
GO; GO:0044306; C:neuron projection terminus; IEA:Ensembl.
GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
GO; GO:0005654; C:nucleoplasm; IDA:HPA.
GO; GO:0031694; F:alpha-2A adrenergic receptor binding; IPI:BHF-UCL.
GO; GO:0004197; F:cysteine-type endopeptidase activity; IDA:UniProtKB.
GO; GO:0016874; F:ligase activity; IEA:UniProtKB-KW.
GO; GO:0008242; F:omega peptidase activity; IDA:UniProtKB.
GO; GO:0004843; F:thiol-dependent ubiquitin-specific protease activity; IBA:GO_Central.
GO; GO:0036459; F:thiol-dependent ubiquitinyl hydrolase activity; TAS:Reactome.
GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB.
GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:ParkinsonsUK-UCL.
GO; GO:0007628; P:adult walking behavior; IEA:Ensembl.
GO; GO:0007412; P:axon target recognition; IEA:Ensembl.
GO; GO:0019896; P:axonal transport of mitochondrion; IEA:Ensembl.
GO; GO:0008283; P:cell proliferation; IEA:Ensembl.
GO; GO:0042755; P:eating behavior; IEA:Ensembl.
GO; GO:0048747; P:muscle fiber development; IEA:Ensembl.
GO; GO:0043407; P:negative regulation of MAP kinase activity; IDA:BHF-UCL.
GO; GO:0050905; P:neuromuscular process; IEA:Ensembl.
GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; NAS:ParkinsonsUK-UCL.
GO; GO:0016579; P:protein deubiquitination; IDA:UniProtKB.
GO; GO:0016241; P:regulation of macroautophagy; TAS:ParkinsonsUK-UCL.
GO; GO:0002931; P:response to ischemia; IEA:Ensembl.
GO; GO:0019233; P:sensory perception of pain; IEA:Ensembl.
Gene3D; 3.40.532.10; -; 1.
InterPro; IPR001578; Peptidase_C12_UCH.
InterPro; IPR030297; UCHL1.
PANTHER; PTHR10589; PTHR10589; 1.
PANTHER; PTHR10589:SF33; PTHR10589:SF33; 1.
Pfam; PF01088; Peptidase_C12; 1.
PRINTS; PR00707; UBCTHYDRLASE.
PROSITE; PS00140; UCH_1; 1.
1: Evidence at protein level;
3D-structure; Complete proteome; Cytoplasm; Direct protein sequencing;
Disease mutation; Endoplasmic reticulum; Glycoprotein;
Hereditary spastic paraplegia; Hydrolase; Ligase; Lipoprotein;
Membrane; Neurodegeneration; Oxidation; Parkinson disease;
Parkinsonism; Phosphoprotein; Polymorphism; Prenylation; Protease;
Reference proteome; Thiol protease; Ubl conjugation pathway.
CHAIN 1 220 Ubiquitin carboxyl-terminal hydrolase
isozyme L1.
/FTId=PRO_0000211055.
PROPEP 221 223 Removed in mature form. {ECO:0000305}.
/FTId=PRO_0000414311.
REGION 5 10 Interaction with ubiquitin.
{ECO:0000269|PubMed:20439756}.
REGION 211 216 Interaction with ubiquitin.
{ECO:0000269|PubMed:20439756}.
ACT_SITE 90 90 Nucleophile.
{ECO:0000269|PubMed:20439756}.
ACT_SITE 161 161 Proton donor.
{ECO:0000269|PubMed:20439756}.
SITE 1 1 Susceptible to oxidation.
{ECO:0000269|PubMed:14722078}.
SITE 6 6 Susceptible to oxidation.
{ECO:0000269|PubMed:14722078}.
SITE 12 12 Susceptible to oxidation.
{ECO:0000269|PubMed:14722078}.
SITE 124 124 Susceptible to oxidation.
{ECO:0000269|PubMed:14722078}.
SITE 176 176 Important for enzyme activity.
{ECO:0000269|PubMed:8639624}.
SITE 179 179 Susceptible to oxidation.
{ECO:0000269|PubMed:14722078}.
SITE 220 220 Susceptible to oxidation.
{ECO:0000269|PubMed:14722078}.
MOD_RES 125 125 Phosphoserine.
{ECO:0000250|UniProtKB:Q00981}.
LIPID 220 220 S-farnesyl cysteine.
{ECO:0000269|PubMed:19261853}.
VARIANT 7 7 E -> A (in SPG79; has decreased binding
to ubiquitin and significantly decreased
hydrolase activity compared to wild-type;
dbSNP:rs397515634).
{ECO:0000269|PubMed:23359680}.
/FTId=VAR_070875.
VARIANT 18 18 S -> 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; dbSNP:rs5030732).
{ECO:0000269|PubMed:10203348,
ECO:0000269|PubMed:11027850,
ECO:0000269|PubMed:12408865,
ECO:0000269|PubMed:12705903,
ECO:0000269|PubMed:15048890,
ECO:0000269|PubMed:16450370,
ECO:0000269|PubMed:18411255,
ECO:0000269|PubMed:21268678}.
/FTId=VAR_015677.
VARIANT 93 93 I -> M (in PARK5; impaired enzymatic
hydrolase activity; has about a 50%
reduction in catalytic activity compared
to wild-type protein; dbSNP:rs121917767).
{ECO:0000269|PubMed:10454131,
ECO:0000269|PubMed:12408865,
ECO:0000269|PubMed:12705903,
ECO:0000269|PubMed:9774100}.
/FTId=VAR_015678.
VARIANT 178 178 R -> Q (in SPG79; increased hydrolase
activity; decreased protein abundance;
dbSNP:rs768996179).
{ECO:0000269|PubMed:28007905}.
/FTId=VAR_078119.
VARIANT 216 216 A -> D (in SPG79; decreased protein
abundance).
{ECO:0000269|PubMed:28007905}.
/FTId=VAR_078120.
MUTAGEN 73 73 Q->R: No effect on enzymatic parameters.
{ECO:0000269|PubMed:8639624}.
MUTAGEN 90 90 C->S: Abolishes enzymatic activity.
{ECO:0000269|PubMed:12705903,
ECO:0000269|PubMed:20439756,
ECO:0000269|PubMed:8639624}.
MUTAGEN 97 97 H->Q,N: 2-fold increase in affinity for
ubiquitin ethyl ester, slight reduction
in enzymatic activity.
{ECO:0000269|PubMed:8639624}.
MUTAGEN 161 161 H->D: 10000-fold decrease in enzymatic
activity; no change in affinity for
ubiquitin ethyl ester.
{ECO:0000269|PubMed:8639624}.
MUTAGEN 161 161 H->K,Q,N,Y: Abolishes enzymatic activity.
{ECO:0000269|PubMed:8639624}.
MUTAGEN 176 176 D->N: 6-fold decrease in affinity for
ubiquitin ethyl ester; 97.5% decrease in
enzymatic activity.
{ECO:0000269|PubMed:8639624}.
MUTAGEN 204 204 F->A: Almost complete loss of activity.
{ECO:0000269|PubMed:20439756}.
HELIX 10 19 {ECO:0000244|PDB:4JKJ}.
STRAND 22 30 {ECO:0000244|PDB:4JKJ}.
HELIX 36 38 {ECO:0000244|PDB:4JKJ}.
STRAND 39 42 {ECO:0000244|PDB:4JKJ}.
STRAND 46 54 {ECO:0000244|PDB:4JKJ}.
HELIX 57 70 {ECO:0000244|PDB:4JKJ}.
TURN 71 74 {ECO:0000244|PDB:4JKJ}.
STRAND 86 88 {ECO:0000244|PDB:2LEN}.
HELIX 90 100 {ECO:0000244|PDB:4JKJ}.
TURN 101 105 {ECO:0000244|PDB:4JKJ}.
HELIX 113 120 {ECO:0000244|PDB:4JKJ}.
TURN 121 123 {ECO:0000244|PDB:4JKJ}.
HELIX 126 134 {ECO:0000244|PDB:4JKJ}.
HELIX 137 147 {ECO:0000244|PDB:4JKJ}.
STRAND 160 168 {ECO:0000244|PDB:4JKJ}.
STRAND 171 175 {ECO:0000244|PDB:4JKJ}.
STRAND 179 181 {ECO:0000244|PDB:4JKJ}.
STRAND 183 187 {ECO:0000244|PDB:4JKJ}.
HELIX 190 192 {ECO:0000244|PDB:4JKJ}.
HELIX 193 207 {ECO:0000244|PDB:4JKJ}.
HELIX 211 213 {ECO:0000244|PDB:2LEN}.
STRAND 215 221 {ECO:0000244|PDB:4JKJ}.
SEQUENCE 223 AA; 24824 MW; C9E972AC4DA5DA8A CRC64;
MQLKPMEINP EMLNKVLSRL GVAGQWRFVD VLGLEEESLG SVPAPACALL LLFPLTAQHE
NFRKKQIEEL KGQEVSPKVY FMKQTIGNSC GTIGLIHAVA NNQDKLGFED GSVLKQFLSE
TEKMSPEDRA KCFEKNEAIQ AAHDAVAQEG QCRVDDKVNF HFILFNNVDG HLYELDGRMP
FPVNHGASSE DTLLKDAAKV CREFTEREQG EVRFSAVALC KAA


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