UCHL1_HUMAN
ID UCHL1_HUMAN Reviewed; 223 AA.
AC P09936; Q4W5K6; Q71UM0;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1990, sequence version 2.
DT 03-AUG-2022, entry version 231.
DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase isozyme L1;
DE Short=UCH-L1;
DE EC=3.4.19.12 {ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:16475834, ECO:0000269|PubMed:20439756, ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100};
DE AltName: Full=Neuron cytoplasmic protein 9.5;
DE AltName: Full=PGP 9.5;
DE Short=PGP9.5;
DE AltName: Full=Ubiquitin thioesterase L1;
DE Flags: Precursor;
GN Name=UCHL1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung, and Muscle;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-15.
RX PubMed=2163617; DOI=10.1042/bj2680521;
RA Day I.N.M., Hinks L.J., Thompson R.J.;
RT "The structure of the human gene encoding protein gene product 9.5
RT (PGP9.5), a neuron-specific ubiquitin C-terminal hydrolase.";
RL Biochem. J. 268:521-524(1990).
RN [5]
RP PROTEIN SEQUENCE OF 1-15 AND 214-221, SUSCEPTIBILITY TO OXIDATION,
RP IDENTIFICATION BY MASS SPECTROMETRY, AND TISSUE SPECIFICITY.
RX PubMed=14722078; DOI=10.1074/jbc.m314124200;
RA Choi J., Levey A.I., Weintraub S.T., Rees H.D., Gearing M., Chin L.-S.,
RA Li L.;
RT "Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal
RT hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's
RT diseases.";
RL J. Biol. Chem. 279:13256-13264(2004).
RN [6]
RP PROTEIN SEQUENCE OF 1-15; 20-27; 66-78; 84-129; 136-195 AND 214-221, AND
RP IDENTIFICATION BY MASS SPECTROMETRY.
RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA Lubec G., Afjehi-Sadat L., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 7-223, AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=2947814; DOI=10.1016/0014-5793(87)81327-3;
RA Day I.N.M., Thompson R.J.;
RT "Molecular cloning of cDNA coding for human PGP 9.5 protein. A novel
RT cytoplasmic marker for neurones and neuroendocrine cells.";
RL FEBS Lett. 210:157-160(1987).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 16-223, FUNCTION, CATALYTIC ACTIVITY,
RP BIOPHYSICOCHEMICAL PROPERTIES, VARIANT PARK5 MET-93, AND CHARACTERIZATION
RP OF VARIANT PARK5 MET-93.
RX PubMed=9774100; DOI=10.1038/26652;
RA Leroy E., Boyer R., Auburger G., Leube B., Ulm G., Mezey E., Harta G.,
RA Brownstein M.J., Jonnalagada S., Chernova T., Dehejia A., Lavedan C.,
RA Gasser T., Steinbach P.J., Wilkinson K.D., Polymeropoulos M.H.;
RT "The ubiquitin pathway in Parkinson's disease.";
RL Nature 395:451-452(1998).
RN [9]
RP PROTEIN SEQUENCE OF 20-25; 79-81; 106-121 AND 134-151.
RX PubMed=1849484; DOI=10.1016/0014-5793(91)80300-r;
RA Honore B., Rasmussen H.H., Vandekerckhove J., Celis J.E.;
RT "Neuronal protein gene product 9.5 (IEF SSP 6104) is expressed in cultured
RT human MRC-5 fibroblasts of normal origin and is strongly down-regulated in
RT their SV40 transformed counterparts.";
RL FEBS Lett. 280:235-240(1991).
RN [10]
RP PROTEIN SEQUENCE OF 20-25; 79-91; 106-123 AND 136-151.
RX PubMed=1286667; DOI=10.1002/elps.11501301199;
RA Rasmussen H.H., van Damme J., Puype M., Gesser B., Celis J.E.,
RA Vandekerckhove J.;
RT "Microsequences of 145 proteins recorded in the two-dimensional gel protein
RT database of normal human epidermal keratinocytes.";
RL Electrophoresis 13:960-969(1992).
RN [11]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, MUTAGENESIS OF GLN-73; CYS-90;
RP HIS-97; HIS-161 AND ASP-176, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=8639624; DOI=10.1021/bi960099f;
RA Larsen C.N., Price J.S., Wilkinson K.D.;
RT "Substrate binding and catalysis by ubiquitin C-terminal hydrolases:
RT identification of two active site residues.";
RL Biochemistry 35:6735-6744(1996).
RN [12]
RP TISSUE SPECIFICITY.
RX PubMed=9790970; DOI=10.1006/bbrc.1998.9532;
RA Wada H., Kito K., Caskey L.S., Yeh E.T.H., Kamitani T.;
RT "Cleavage of the C-terminus of NEDD8 by UCH-L3.";
RL Biochem. Biophys. Res. Commun. 251:688-692(1998).
RN [13]
RP FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANT PARK5 MET-93, AND
RP CHARACTERIZATION OF VARIANT TYR-18.
RX PubMed=12408865; DOI=10.1016/s0092-8674(02)01012-7;
RA Liu Y., Fallon L., Lashuel H.A., Liu Z., Lansbury P.T. Jr.;
RT "The UCH-L1 gene encodes two opposing enzymatic activities that affect
RT alpha-synuclein degradation and Parkinson's disease susceptibility.";
RL Cell 111:209-218(2002).
RN [14]
RP INTERACTION WITH COPS5.
RX PubMed=12082530; DOI=10.1038/sj.onc.1205390;
RA Caballero O.L., Resto V., Patturajan M., Meerzaman D., Guo M.Z., Engles J.,
RA Yochem R., Ratovitski E., Sidransky D., Jen J.;
RT "Interaction and colocalization of PGP9.5 with JAB1 and p27(Kip1).";
RL Oncogene 21:3003-3010(2002).
RN [15]
RP CATALYTIC ACTIVITY, AND ACTIVE SITE.
RX PubMed=16475834; DOI=10.1021/bi052135t;
RA Case A., Stein R.L.;
RT "Mechanistic studies of ubiquitin C-terminal hydrolase L1.";
RL Biochemistry 45:2443-2452(2006).
RN [16]
RP SUBCELLULAR LOCATION, AND ISOPRENYLATION AT CYS-220.
RX PubMed=19261853; DOI=10.1073/pnas.0806474106;
RA Liu Z., Meray R.K., Grammatopoulos T.N., Fredenburg R.A., Cookson M.R.,
RA Liu Y., Logan T., Lansbury P.T. Jr.;
RT "Membrane-associated farnesylated UCH-L1 promotes alpha-synuclein
RT neurotoxicity and is a therapeutic target for Parkinson's disease.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:4635-4640(2009).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [19]
RP FUNCTION, CATALYTIC ACTIVITY, VARIANTS SPG79 ALA-7 AND MET-93,
RP CHARACTERIZATION OF VARIANT SPG79 ALA-7, AND MUTAGENESIS OF CYS-90.
RX PubMed=23359680; DOI=10.1073/pnas.1222732110;
RA Bilguvar K., Tyagi N.K., Ozkara C., Tuysuz B., Bakircioglu M., Choi M.,
RA Delil S., Caglayan A.O., Baranoski J.F., Erturk O., Yalcinkaya C.,
RA Karacorlu M., Dincer A., Johnson M.H., Mane S., Chandra S.S., Louvi A.,
RA Boggon T.J., Lifton R.P., Horwich A.L., Gunel M.;
RT "Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads
RT to early-onset progressive neurodegeneration.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:3489-3494(2013).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS), AND SUBUNIT.
RX PubMed=16537382; DOI=10.1073/pnas.0510403103;
RA Das C., Hoang Q.Q., Kreinbring C.A., Luchansky S.J., Meray R.K., Ray S.S.,
RA Lansbury P.T., Ringe D., Petsko G.A.;
RT "Structural basis for conformational plasticity of the Parkinson's disease-
RT associated ubiquitin hydrolase UCH-L1.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:4675-4680(2006).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF VARIANTS TYR-18 AND MET-93 IN
RP COMPLEX WITH UBIQUITIN, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF
RP CYS-90 AND PHE-204.
RX PubMed=20439756; DOI=10.1073/pnas.0910870107;
RA Boudreaux D.A., Maiti T.K., Davies C.W., Das C.;
RT "Ubiquitin vinyl methyl ester binding orients the misaligned active site of
RT the ubiquitin hydrolase UCHL1 into productive conformation.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:9117-9122(2010).
RN [22]
RP CHARACTERIZATION OF VARIANT PARK5 MET-93, CHARACTERIZATION OF VARIANT
RP TYR-18, MUTAGENESIS OF CYS-90, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL
RP PROPERTIES.
RX PubMed=12705903; DOI=10.1016/s0006-291x(03)00555-2;
RA Nishikawa K., Li H., Kawamura R., Osaka H., Wang Y.-L., Hara Y.,
RA Hirokawa T., Manago Y., Amano T., Noda M., Aoki S., Wada K.;
RT "Alterations of structure and hydrolase activity of parkinsonism-associated
RT human ubiquitin carboxyl-terminal hydrolase L1 variants.";
RL Biochem. Biophys. Res. Commun. 304:176-183(2003).
RN [23]
RP VARIANT MET-93.
RX PubMed=10454131; DOI=10.1016/s0304-3940(99)00465-6;
RA Harhangi B.S., Farrer M.J., Lincoln S., Bonifati V., Meco G.,
RA De Michele G., Brice A., Durr A., Martinez M., Gasser T., Bereznai B.,
RA Vaughan J.R., Wood N.W., Hardy J., Oostra B.A., Breteler M.M.;
RT "The Ile93Met mutation in the ubiquitin carboxy-terminal-hydrolase-L1 gene
RT is not observed in European cases with familial Parkinson's disease.";
RL Neurosci. Lett. 270:1-4(1999).
RN [24]
RP VARIANT TYR-18.
RX PubMed=10203348; DOI=10.1097/00001756-199902050-00040;
RA Lincoln S., Vaughan J., Wood N., Baker M., Adamson J., Gwinn-Hardy K.,
RA Lynch T., Hardy J., Farrer M.;
RT "Low frequency of pathogenic mutations in the ubiquitin carboxy-terminal
RT hydrolase gene in familial Parkinson's disease.";
RL NeuroReport 10:427-429(1999).
RN [25]
RP VARIANT TYR-18.
RX PubMed=11027850; DOI=10.1016/s0304-3940(00)01510-x;
RA Mellick G.D., Silburn P.A.;
RT "The ubiquitin carboxy-terminal hydrolase-L1 gene S18Y polymorphism does
RT not confer protection against idiopathic Parkinson's disease.";
RL Neurosci. Lett. 293:127-130(2000).
RN [26]
RP VARIANT TYR-18.
RX PubMed=15048890; DOI=10.1002/ana.20017;
RG UCHL1 global genetics consortium;
RA Maraganore D.M., Lesnick T.G., Elbaz A., Chartier-Harlin M.-C., Gasser T.,
RA Krueger R., Hattori N., Mellick G.D., Quattrone A., Satoh J., Toda T.,
RA Wang J., Ioannidis J.P.A., de Andrade M., Rocca W.A.;
RT "UCHL1 is a Parkinson's disease susceptibility gene.";
RL Ann. Neurol. 55:512-521(2004).
RN [27]
RP ERRATUM OF PUBMED:15048890.
RG UCHL1 global genetics consortium;
RA Maraganore D.M., Lesnick T.G., Elbaz A., Chartier-Harlin M.-C., Gasser T.,
RA Krueger R., Hattori N., Mellick G.D., Quattrone A., Satoh J., Toda T.,
RA Wang J., Ioannidis J.P.A., de Andrade M., Rocca W.A.;
RL Ann. Neurol. 55:899-899(2004).
RN [28]
RP VARIANT TYR-18, AND LACK OF ASSOCIATION OF VARIANT TYR-18 WITH PARKINSON
RP DISEASE.
RX PubMed=16450370; DOI=10.1002/ana.20757;
RA Healy D.G., Abou-Sleiman P.M., Casas J.P., Ahmadi K.R., Lynch T.,
RA Gandhi S., Muqit M.M., Foltynie T., Barker R., Bhatia K.P., Quinn N.P.,
RA Lees A.J., Gibson J.M., Holton J.L., Revesz T., Goldstein D.B., Wood N.W.;
RT "UCHL-1 is not a Parkinson's disease susceptibility gene.";
RL Ann. Neurol. 59:627-633(2006).
RN [29]
RP CHARACTERIZATION OF VARIANT TYR-18, AND ANTIOXIDANT FUNCTION IN NEURONAL
RP CELLS.
RX PubMed=18411255; DOI=10.1093/hmg/ddn115;
RA Kyratzi E., Pavlaki M., Stefanis L.;
RT "The S18Y polymorphic variant of UCH-L1 confers an antioxidant function to
RT neuronal cells.";
RL Hum. Mol. Genet. 17:2160-2171(2008).
RN [30]
RP VARIANT TYR-18.
RX PubMed=21268678; DOI=10.3109/13816810.2010.544360;
RA Rudolph T., Sjolander A., Palmer M.S., Minthon L., Wallin A., Andreasen N.,
RA Tasa G., Juronen E., Blennow K., Zetterberg H., Zetterberg M.;
RT "Ubiquitin carboxyl-terminal esterase L1 (UCHL1) S18Y polymorphism in
RT patients with cataracts.";
RL Ophthalmic Genet. 32:75-79(2011).
RN [31]
RP VARIANTS SPG79 GLN-178 AND ASP-216, AND CHARACTERIZATION OF VARIANTS SPG79
RP GLN-178 AND ASP-216.
RX PubMed=28007905; DOI=10.1093/hmg/ddw391;
RA Rydning S.L., Backe P.H., Sousa M.M., Iqbal Z., Oeye A.M., Sheng Y.,
RA Yang M., Lin X., Slupphaug G., Nordenmark T.H., Vigeland M.D., Bjoeraas M.,
RA Tallaksen C.M., Selmer K.K.;
RT "Novel UCHL1 mutations reveal new insights into ubiquitin processing.";
RL Hum. Mol. Genet. 26:1031-1040(2017).
CC -!- FUNCTION: Ubiquitin-protein hydrolase involved both in the processing
CC of ubiquitin precursors and of ubiquitinated proteins (Probable). This
CC enzyme is a thiol protease that recognizes and hydrolyzes a peptide
CC bond at the C-terminal glycine of ubiquitin (PubMed:9774100,
CC PubMed:8639624, PubMed:12408865, PubMed:23359680). Also binds to free
CC monoubiquitin and may prevent its degradation in lysosomes (By
CC similarity). The homodimer may have ATP-independent ubiquitin ligase
CC activity (PubMed:12408865). {ECO:0000250|UniProtKB:Q9R0P9,
CC ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:23359680,
CC ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100,
CC ECO:0000305|PubMed:12408865, ECO:0000305|PubMed:23359680,
CC ECO:0000305|PubMed:8639624, ECO:0000305|PubMed:9774100}.
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:0000269|PubMed:12408865,
CC ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:16475834,
CC ECO:0000269|PubMed:20439756, ECO:0000269|PubMed:23359680,
CC ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=122 nM for Ub-AMC {ECO:0000269|PubMed:12705903,
CC ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100};
CC KM=1.20 uM for ubiquitin ethyl ester {ECO:0000269|PubMed:12705903,
CC ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100};
CC Vmax=0.47 umol/min/mg enzyme toward Ub-AMC
CC {ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:8639624,
CC ECO:0000269|PubMed:9774100};
CC Vmax=25 umol/min/mg enzyme toward ubiquitin ethyl ester
CC {ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:8639624,
CC ECO:0000269|PubMed:9774100};
CC -!- SUBUNIT: Monomer. Homodimer. Interacts with SNCA (By similarity).
CC Interacts with COPS5. {ECO:0000250, ECO:0000269|PubMed:12082530,
CC ECO:0000269|PubMed:16537382, ECO:0000269|PubMed:20439756}.
CC -!- INTERACTION:
CC P09936; P63010-2: AP2B1; NbExp=3; IntAct=EBI-714860, EBI-11529439;
CC P09936; P05067: APP; NbExp=5; IntAct=EBI-714860, EBI-77613;
CC P09936; P05067-2: APP; NbExp=3; IntAct=EBI-714860, EBI-17264467;
CC P09936; Q8N6T3-3: ARFGAP1; NbExp=3; IntAct=EBI-714860, EBI-10694449;
CC P09936; P18847: ATF3; NbExp=3; IntAct=EBI-714860, EBI-712767;
CC P09936; Q9H1Y0: ATG5; NbExp=3; IntAct=EBI-714860, EBI-1047414;
CC P09936; O15392: BIRC5; NbExp=3; IntAct=EBI-714860, EBI-518823;
CC P09936; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-714860, EBI-2837444;
CC P09936; P83916: CBX1; NbExp=4; IntAct=EBI-714860, EBI-78129;
CC P09936; P11802: CDK4; NbExp=4; IntAct=EBI-714860, EBI-295644;
CC P09936; Q00535: CDK5; NbExp=2; IntAct=EBI-714860, EBI-1041567;
CC P09936; Q9UNS2: COPS3; NbExp=3; IntAct=EBI-714860, EBI-350590;
CC P09936; Q92905: COPS5; NbExp=3; IntAct=EBI-714860, EBI-594661;
CC P09936; P00533: EGFR; NbExp=3; IntAct=EBI-714860, EBI-297353;
CC P09936; O60739: EIF1B; NbExp=3; IntAct=EBI-714860, EBI-1043343;
CC P09936; Q8TC29: ENKUR; NbExp=3; IntAct=EBI-714860, EBI-9246952;
CC P09936; Q9UI08-2: EVL; NbExp=3; IntAct=EBI-714860, EBI-6448852;
CC P09936; Q8WVV9-3: HNRNPLL; NbExp=3; IntAct=EBI-714860, EBI-25845242;
CC P09936; Q14164: IKBKE; NbExp=3; IntAct=EBI-714860, EBI-307369;
CC P09936; Q6DN90-2: IQSEC1; NbExp=3; IntAct=EBI-714860, EBI-21911304;
CC P09936; Q96JM7-2: L3MBTL3; NbExp=3; IntAct=EBI-714860, EBI-11985629;
CC P09936; P13473-2: LAMP2; NbExp=3; IntAct=EBI-714860, EBI-21591415;
CC P09936; Q9BYZ2: LDHAL6B; NbExp=3; IntAct=EBI-714860, EBI-1108377;
CC P09936; O95777: LSM8; NbExp=3; IntAct=EBI-714860, EBI-347779;
CC P09936; A4FUJ8: MKL1; NbExp=3; IntAct=EBI-714860, EBI-21250407;
CC P09936; Q15843: NEDD8; NbExp=4; IntAct=EBI-714860, EBI-716247;
CC P09936; O15381-5: NVL; NbExp=3; IntAct=EBI-714860, EBI-18577082;
CC P09936; Q9BR81: PCDHGC3; NbExp=3; IntAct=EBI-714860, EBI-22012354;
CC P09936; Q13113: PDZK1IP1; NbExp=3; IntAct=EBI-714860, EBI-716063;
CC P09936; P62826: RAN; NbExp=3; IntAct=EBI-714860, EBI-286642;
CC P09936; Q8TAI7: RHEBL1; NbExp=3; IntAct=EBI-714860, EBI-746555;
CC P09936; Q9ULX5: RNF112; NbExp=3; IntAct=EBI-714860, EBI-25829984;
CC P09936; Q15554-4: TERF2; NbExp=3; IntAct=EBI-714860, EBI-25840535;
CC P09936; Q9NYB0: TERF2IP; NbExp=2; IntAct=EBI-714860, EBI-750109;
CC P09936; P04637: TP53; NbExp=3; IntAct=EBI-714860, EBI-366083;
CC P09936; Q9Y4K3: TRAF6; NbExp=3; IntAct=EBI-714860, EBI-359276;
CC P09936; P19474: TRIM21; NbExp=3; IntAct=EBI-714860, EBI-81290;
CC P09936; Q9BSL1: UBAC1; NbExp=3; IntAct=EBI-714860, EBI-749370;
CC P09936; Q7KZS0: UBE2I; NbExp=3; IntAct=EBI-714860, EBI-10180829;
CC P09936; P61086: UBE2K; NbExp=3; IntAct=EBI-714860, EBI-473850;
CC P09936; Q9UK80: USP21; NbExp=4; IntAct=EBI-714860, EBI-373242;
CC P09936; Q86WB0-2: ZC3HC1; NbExp=3; IntAct=EBI-714860, EBI-25894765;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19261853}.
CC Endoplasmic reticulum membrane {ECO:0000269|PubMed:19261853}; Lipid-
CC anchor {ECO:0000269|PubMed:19261853}. Note=About 30% of total UCHL1 is
CC associated with membranes in brain.
CC -!- TISSUE SPECIFICITY: Found in neuronal cell bodies and processes
CC throughout the neocortex (at protein level). Expressed in neurons and
CC cells of the diffuse neuroendocrine system and their tumors. Weakly
CC expressed in ovary. Down-regulated in brains from Parkinson disease and
CC Alzheimer disease patients. {ECO:0000269|PubMed:14722078,
CC ECO:0000269|PubMed:9790970}.
CC -!- PTM: O-glycosylated. {ECO:0000250}.
CC -!- DISEASE: Parkinson disease 5 (PARK5) [MIM:613643]: A complex
CC neurodegenerative disorder with manifestations ranging from typical
CC Parkinson disease to dementia with Lewy bodies. Clinical features
CC include parkinsonian symptoms (resting tremor, rigidity, postural
CC instability and bradykinesia), dementia, diffuse Lewy body pathology,
CC autonomic dysfunction, hallucinations and paranoia.
CC {ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903,
CC ECO:0000269|PubMed:9774100}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Spastic paraplegia 79, autosomal recessive (SPG79)
CC [MIM:615491]: A form of spastic paraplegia, a neurodegenerative
CC disorder characterized by a slow, gradual, progressive weakness and
CC spasticity of the lower limbs. Rate of progression and the severity of
CC symptoms are quite variable. Initial symptoms may include difficulty
CC with balance, weakness and stiffness in the legs, muscle spasms, and
CC dragging the toes when walking. In some forms of the disorder, bladder
CC symptoms (such as incontinence) may appear, or the weakness and
CC stiffness may spread to other parts of the body. SPG79 is characterized
CC by childhood onset blindness, cerebellar ataxia, nystagmus, dorsal
CC column dysfunction, and spasticity with upper motor neuron dysfunction.
CC {ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:28007905}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- MISCELLANEOUS: Oxidation of Met-1, Met-6, Met-12, Met-124 and Met-179
CC to methionine sulfoxide, and oxidation of Cys-220 to cysteine sulfonic
CC acid have been observed in brains from Alzheimer disease (AD) and
CC Parkinson disease (PD) patients. In AD, UCHL1 was found to be
CC associated with neurofibrillary tangles. In contrast to UCHL3, does not
CC hydrolyze a peptide bond at the C-terminal glycine of NEDD8.
CC -!- SIMILARITY: Belongs to the peptidase C12 family. {ECO:0000305}.
CC -!- CAUTION: PubMed:9774100 reports the association of mutation Ile93Met
CC with Parkinson disease. However, according to PubMed:16450370 this
CC association is uncertain and UCHL1 is not a susceptibility gene for
CC Parkinson disease. {ECO:0000305}.
CC -!- CAUTION: The oxidation forms of Met-1, Met-6, Met-12, Met-124, Met-179
CC and Cys-220 are subject of controversy and could be the artifactual
CC results of sample handling. {ECO:0000305|PubMed:14722078}.
CC -!- CAUTION: The homodimer may have ATP-independent ubiquitin ligase
CC activity (PubMed:12408865). However, in another study, UCHL1 was shown
CC to lack ubiquitin ligase activity (PubMed:23359680).
CC {ECO:0000269|PubMed:23359680, ECO:0000305|PubMed:12408865}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA28443.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Ubiquitin carboxy-terminal hydrolase
CC L1 entry;
CC URL="https://en.wikipedia.org/wiki/Ubiquitin_carboxy-terminal_hydrolase_L1";
CC ---------------------------------------------------------------------------
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DR EMBL; AC095043; AAY40923.1; -; Genomic_DNA.
DR EMBL; CH471069; EAW92983.1; -; Genomic_DNA.
DR EMBL; BC000332; AAH00332.1; -; mRNA.
DR EMBL; BC005117; AAH05117.1; -; mRNA.
DR EMBL; BC006305; AAH06305.1; -; mRNA.
DR EMBL; X17377; CAA35249.1; -; Genomic_DNA.
DR EMBL; X04741; CAA28443.1; ALT_INIT; mRNA.
DR EMBL; AH007277; AAD09172.1; -; Genomic_DNA.
DR CCDS; CCDS3462.1; -.
DR PIR; A25856; A25856.
DR RefSeq; NP_004172.2; NM_004181.4.
DR PDB; 2ETL; X-ray; 2.40 A; A/B=1-223.
DR PDB; 2LEN; NMR; -; A=1-223.
DR PDB; 3IFW; X-ray; 2.40 A; A=1-223.
DR PDB; 3IRT; X-ray; 2.80 A; A/B=1-223.
DR PDB; 3KVF; X-ray; 2.80 A; A=1-223.
DR PDB; 3KW5; X-ray; 2.83 A; A=1-223.
DR PDB; 4DM9; X-ray; 2.35 A; A/B=1-223.
DR PDB; 4JKJ; X-ray; 2.15 A; A/B=1-223.
DR PDBsum; 2ETL; -.
DR PDBsum; 2LEN; -.
DR PDBsum; 3IFW; -.
DR PDBsum; 3IRT; -.
DR PDBsum; 3KVF; -.
DR PDBsum; 3KW5; -.
DR PDBsum; 4DM9; -.
DR PDBsum; 4JKJ; -.
DR AlphaFoldDB; P09936; -.
DR BMRB; P09936; -.
DR SMR; P09936; -.
DR BioGRID; 113192; 213.
DR CORUM; P09936; -.
DR DIP; DIP-36620N; -.
DR IntAct; P09936; 79.
DR MINT; P09936; -.
DR STRING; 9606.ENSP00000284440; -.
DR BindingDB; P09936; -.
DR ChEMBL; CHEMBL6159; -.
DR DrugBank; DB12695; Phenethyl Isothiocyanate.
DR GuidetoPHARMACOLOGY; 2426; -.
DR MEROPS; C12.001; -.
DR GlyGen; P09936; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P09936; -.
DR MetOSite; P09936; -.
DR PhosphoSitePlus; P09936; -.
DR SwissPalm; P09936; -.
DR BioMuta; UCHL1; -.
DR DMDM; 136681; -.
DR DOSAC-COBS-2DPAGE; P09936; -.
DR UCD-2DPAGE; P09936; -.
DR CPTAC; CPTAC-601; -.
DR CPTAC; CPTAC-602; -.
DR EPD; P09936; -.
DR jPOST; P09936; -.
DR MassIVE; P09936; -.
DR PaxDb; P09936; -.
DR PeptideAtlas; P09936; -.
DR PRIDE; P09936; -.
DR ProteomicsDB; 52282; -.
DR TopDownProteomics; P09936; -.
DR Antibodypedia; 1062; 2211 antibodies from 52 providers.
DR DNASU; 7345; -.
DR Ensembl; ENST00000284440.9; ENSP00000284440.4; ENSG00000154277.13.
DR Ensembl; ENST00000503431.5; ENSP00000422542.1; ENSG00000154277.13.
DR GeneID; 7345; -.
DR KEGG; hsa:7345; -.
DR MANE-Select; ENST00000284440.9; ENSP00000284440.4; NM_004181.5; NP_004172.2.
DR CTD; 7345; -.
DR DisGeNET; 7345; -.
DR GeneCards; UCHL1; -.
DR HGNC; HGNC:12513; UCHL1.
DR HPA; ENSG00000154277; Group enriched (brain, pituitary gland).
DR MalaCards; UCHL1; -.
DR MIM; 191342; gene.
DR MIM; 613643; phenotype.
DR MIM; 615491; phenotype.
DR neXtProt; NX_P09936; -.
DR OpenTargets; ENSG00000154277; -.
DR Orphanet; 352654; Early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome.
DR Orphanet; 2828; Young-onset Parkinson disease.
DR PharmGKB; PA37160; -.
DR VEuPathDB; HostDB:ENSG00000154277; -.
DR eggNOG; KOG1415; Eukaryota.
DR GeneTree; ENSGT00940000157306; -.
DR HOGENOM; CLU_054406_2_0_1; -.
DR InParanoid; P09936; -.
DR OMA; HACGLIA; -.
DR OrthoDB; 1013351at2759; -.
DR PhylomeDB; P09936; -.
DR TreeFam; TF316166; -.
DR BRENDA; 3.4.19.12; 2681.
DR PathwayCommons; P09936; -.
DR Reactome; R-HSA-5689603; UCH proteinases.
DR SABIO-RK; P09936; -.
DR SignaLink; P09936; -.
DR SIGNOR; P09936; -.
DR BioGRID-ORCS; 7345; 9 hits in 1118 CRISPR screens.
DR ChiTaRS; UCHL1; human.
DR EvolutionaryTrace; P09936; -.
DR GeneWiki; Ubiquitin_carboxy-terminal_hydrolase_L1; -.
DR GenomeRNAi; 7345; -.
DR Pharos; P09936; Tchem.
DR PRO; PR:P09936; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; P09936; protein.
DR Bgee; ENSG00000154277; Expressed in pons and 167 other tissues.
DR ExpressionAtlas; P09936; baseline and differential.
DR Genevisible; P09936; HS.
DR GO; GO:1904115; C:axon cytoplasm; IEA:GOC.
DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0044306; C:neuron projection terminus; IEA:Ensembl.
DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0031694; F:alpha-2A adrenergic receptor binding; IPI:BHF-UCL.
DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:UniProtKB.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0016874; F:ligase activity; IEA:InterPro.
DR GO; GO:0008242; F:omega peptidase activity; IDA:UniProtKB.
DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:ParkinsonsUK-UCL.
DR GO; GO:0007628; P:adult walking behavior; IEA:Ensembl.
DR GO; GO:0007412; P:axon target recognition; IEA:Ensembl.
DR GO; GO:0019896; P:axonal transport of mitochondrion; IEA:Ensembl.
DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0042755; P:eating behavior; IEA:Ensembl.
DR GO; GO:0002176; P:male germ cell proliferation; IEA:Ensembl.
DR GO; GO:0055001; P:muscle cell development; IEA:Ensembl.
DR GO; GO:0043407; P:negative regulation of MAP kinase activity; IDA:BHF-UCL.
DR GO; GO:0050905; P:neuromuscular process; IEA:Ensembl.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; NAS:ParkinsonsUK-UCL.
DR GO; GO:0016579; P:protein deubiquitination; IDA:UniProtKB.
DR GO; GO:0016241; P:regulation of macroautophagy; TAS:ParkinsonsUK-UCL.
DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl.
DR GO; GO:0019233; P:sensory perception of pain; IEA:Ensembl.
DR Gene3D; 3.40.532.10; -; 1.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR InterPro; IPR001578; Peptidase_C12_UCH.
DR InterPro; IPR036959; Peptidase_C12_UCH_sf.
DR InterPro; IPR030297; UCHL1.
DR PANTHER; PTHR10589; PTHR10589; 1.
DR PANTHER; PTHR10589:SF19; PTHR10589:SF19; 1.
DR Pfam; PF01088; Peptidase_C12; 1.
DR PRINTS; PR00707; UBCTHYDRLASE.
DR SUPFAM; SSF54001; SSF54001; 1.
DR PROSITE; PS00140; UCH_1; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cytoplasm; Direct protein sequencing; Disease variant;
KW Endoplasmic reticulum; Glycoprotein; Hereditary spastic paraplegia;
KW Hydrolase; Lipoprotein; Membrane; Neurodegeneration; Oxidation;
KW Parkinson disease; Parkinsonism; Phosphoprotein; Prenylation; Protease;
KW Reference proteome; Thiol protease; Ubl conjugation pathway.
FT CHAIN 1..220
FT /note="Ubiquitin carboxyl-terminal hydrolase isozyme L1"
FT /id="PRO_0000211055"
FT PROPEP 221..223
FT /note="Removed in mature form"
FT /evidence="ECO:0000305"
FT /id="PRO_0000414311"
FT REGION 5..10
FT /note="Interaction with ubiquitin"
FT /evidence="ECO:0000269|PubMed:20439756"
FT REGION 211..216
FT /note="Interaction with ubiquitin"
FT /evidence="ECO:0000269|PubMed:20439756"
FT ACT_SITE 90
FT /note="Nucleophile"
FT /evidence="ECO:0000269|PubMed:20439756"
FT ACT_SITE 161
FT /note="Proton donor"
FT /evidence="ECO:0000269|PubMed:20439756"
FT SITE 1
FT /note="Susceptible to oxidation"
FT /evidence="ECO:0000269|PubMed:14722078"
FT SITE 6
FT /note="Susceptible to oxidation"
FT /evidence="ECO:0000269|PubMed:14722078"
FT SITE 12
FT /note="Susceptible to oxidation"
FT /evidence="ECO:0000269|PubMed:14722078"
FT SITE 124
FT /note="Susceptible to oxidation"
FT /evidence="ECO:0000269|PubMed:14722078"
FT SITE 176
FT /note="Important for enzyme activity"
FT /evidence="ECO:0000269|PubMed:8639624"
FT SITE 179
FT /note="Susceptible to oxidation"
FT /evidence="ECO:0000269|PubMed:14722078"
FT SITE 220
FT /note="Susceptible to oxidation"
FT /evidence="ECO:0000269|PubMed:14722078"
FT MOD_RES 125
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q00981"
FT LIPID 220
FT /note="S-farnesyl cysteine"
FT /evidence="ECO:0000269|PubMed:19261853"
FT VARIANT 7
FT /note="E -> A (in SPG79; has decreased binding to ubiquitin
FT and significantly decreased hydrolase activity compared to
FT wild-type; dbSNP:rs397515634)"
FT /evidence="ECO:0000269|PubMed:23359680"
FT /id="VAR_070875"
FT VARIANT 18
FT /note="S -> Y (may be associated with reduced risk for
FT sporadic Parkinson disease; it confers protection from
FT oxidative stress when expressed at physiological levels in
FT neuroblastoma cells and primary cortical neurons; loss of
FT dimerization ability; impaired ligase activity;
FT dbSNP:rs5030732)"
FT /evidence="ECO:0000269|PubMed:10203348,
FT ECO:0000269|PubMed:11027850, ECO:0000269|PubMed:12408865,
FT ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:15048890,
FT ECO:0000269|PubMed:16450370, ECO:0000269|PubMed:18411255,
FT ECO:0000269|PubMed:21268678"
FT /id="VAR_015677"
FT VARIANT 93
FT /note="I -> M (in PARK5; impaired enzymatic hydrolase
FT activity; has about a 50% reduction in catalytic activity
FT compared to wild-type protein; dbSNP:rs121917767)"
FT /evidence="ECO:0000269|PubMed:10454131,
FT ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903,
FT ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:9774100"
FT /id="VAR_015678"
FT VARIANT 178
FT /note="R -> Q (in SPG79; increased hydrolase activity;
FT decreased protein abundance; dbSNP:rs768996179)"
FT /evidence="ECO:0000269|PubMed:28007905"
FT /id="VAR_078119"
FT VARIANT 216
FT /note="A -> D (in SPG79; decreased protein abundance;
FT dbSNP:rs1057519600)"
FT /evidence="ECO:0000269|PubMed:28007905"
FT /id="VAR_078120"
FT MUTAGEN 73
FT /note="Q->R: No effect on enzymatic parameters."
FT /evidence="ECO:0000269|PubMed:8639624"
FT MUTAGEN 90
FT /note="C->S: Abolishes enzymatic activity."
FT /evidence="ECO:0000269|PubMed:12705903,
FT ECO:0000269|PubMed:20439756, ECO:0000269|PubMed:23359680,
FT ECO:0000269|PubMed:8639624"
FT MUTAGEN 97
FT /note="H->Q,N: 2-fold increase in affinity for ubiquitin
FT ethyl ester, slight reduction in enzymatic activity."
FT /evidence="ECO:0000269|PubMed:8639624"
FT MUTAGEN 161
FT /note="H->D: 10000-fold decrease in enzymatic activity; no
FT change in affinity for ubiquitin ethyl ester."
FT /evidence="ECO:0000269|PubMed:8639624"
FT MUTAGEN 161
FT /note="H->K,Q,N,Y: Abolishes enzymatic activity."
FT /evidence="ECO:0000269|PubMed:8639624"
FT MUTAGEN 176
FT /note="D->N: 6-fold decrease in affinity for ubiquitin
FT ethyl ester; 97.5% decrease in enzymatic activity."
FT /evidence="ECO:0000269|PubMed:8639624"
FT MUTAGEN 204
FT /note="F->A: Almost complete loss of activity."
FT /evidence="ECO:0000269|PubMed:20439756"
FT HELIX 10..19
FT /evidence="ECO:0007829|PDB:4JKJ"
FT STRAND 22..30
FT /evidence="ECO:0007829|PDB:4JKJ"
FT HELIX 36..38
FT /evidence="ECO:0007829|PDB:4JKJ"
FT STRAND 39..42
FT /evidence="ECO:0007829|PDB:4JKJ"
FT STRAND 46..54
FT /evidence="ECO:0007829|PDB:4JKJ"
FT HELIX 57..70
FT /evidence="ECO:0007829|PDB:4JKJ"
FT TURN 71..74
FT /evidence="ECO:0007829|PDB:4JKJ"
FT STRAND 86..88
FT /evidence="ECO:0007829|PDB:2LEN"
FT HELIX 90..100
FT /evidence="ECO:0007829|PDB:4JKJ"
FT TURN 101..105
FT /evidence="ECO:0007829|PDB:4JKJ"
FT HELIX 113..120
FT /evidence="ECO:0007829|PDB:4JKJ"
FT TURN 121..123
FT /evidence="ECO:0007829|PDB:4JKJ"
FT HELIX 126..134
FT /evidence="ECO:0007829|PDB:4JKJ"
FT HELIX 137..147
FT /evidence="ECO:0007829|PDB:4JKJ"
FT STRAND 160..168
FT /evidence="ECO:0007829|PDB:4JKJ"
FT STRAND 171..175
FT /evidence="ECO:0007829|PDB:4JKJ"
FT STRAND 179..181
FT /evidence="ECO:0007829|PDB:4JKJ"
FT STRAND 183..187
FT /evidence="ECO:0007829|PDB:4JKJ"
FT HELIX 190..192
FT /evidence="ECO:0007829|PDB:4JKJ"
FT HELIX 193..207
FT /evidence="ECO:0007829|PDB:4JKJ"
FT HELIX 211..213
FT /evidence="ECO:0007829|PDB:2LEN"
FT STRAND 215..221
FT /evidence="ECO:0007829|PDB:4JKJ"
SQ 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
