ARSG_HUMAN
ID ARSG_HUMAN Reviewed; 525 AA.
AC Q96EG1; Q6UXF2; Q9Y2K4;
DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 158.
DE RecName: Full=Arylsulfatase G;
DE Short=ASG;
DE EC=3.1.6.1 {ECO:0000269|PubMed:18283100, ECO:0000269|PubMed:29300381};
DE AltName: Full=N-sulfoglucosamine-3-sulfatase;
DE EC=3.1.6.15 {ECO:0000269|PubMed:22689975};
DE Flags: Precursor;
GN Name=ARSG; Synonyms=KIAA1001; ORFNames=UNQ839/PRO1777;
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 MRNA].
RC TISSUE=Brain;
RX PubMed=10231032; DOI=10.1093/dnares/6.1.63;
RA Nagase T., Ishikawa K., Suyama M., Kikuno R., Hirosawa M., Miyajima N.,
RA Tanaka A., Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XIII. The
RT complete sequences of 100 new cDNA clones from brain which code for large
RT proteins in vitro.";
RL DNA Res. 6:63-70(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
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 SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND GLYCOSYLATION.
RX PubMed=12461688; DOI=10.1038/sj.ejhg.5200887;
RA Ferrante P., Messali S., Meroni G., Ballabio A.;
RT "Molecular and biochemical characterisation of a novel sulphatase gene:
RT arylsulfatase G (ARSG).";
RL Eur. J. Hum. Genet. 10:813-818(2002).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, TISSUE SPECIFICITY,
RP OXOALANINE AT CYS-84, GLYCOSYLATION, BIOPHYSICOCHEMICAL PROPERTIES,
RP MUTAGENESIS OF CYS-84 AND ALA-501, AND ACTIVITY REGULATION.
RX PubMed=18283100; DOI=10.1074/jbc.m709917200;
RA Frese M.A., Schulz S., Dierks T.;
RT "Arylsulfatase G, a novel lysosomal sulfatase.";
RL J. Biol. Chem. 283:11388-11395(2008).
RN [6]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=22689975; DOI=10.1073/pnas.1202071109;
RA Kowalewski B., Lamanna W.C., Lawrence R., Damme M., Stroobants S.,
RA Padva M., Kalus I., Frese M.A., Luebke T., Luellmann-Rauch R., D'Hooge R.,
RA Esko J.D., Dierks T.;
RT "Arylsulfatase G inactivation causes loss of heparan sulfate 3-O-sulfatase
RT activity and mucopolysaccharidosis in mice.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:10310-10315(2012).
RN [7]
RP PROTEOLYTIC CLEAVAGE.
RX PubMed=25135642; DOI=10.1074/jbc.m114.584144;
RA Kowalewski B., Luebke T., Kollmann K., Braulke T., Reinheckel T.,
RA Dierks T., Damme M.;
RT "Molecular characterization of arylsulfatase G: expression, processing,
RT glycosylation, transport, and activity.";
RL J. Biol. Chem. 289:27992-28005(2014).
RN [8]
RP INVOLVEMENT IN USH4, VARIANT USH4 TYR-45, CHARACTERIZATION OF VARIANT USH4
RP TYR-45, FUNCTION, CATALYTIC ACTIVITY, AND TISSUE SPECIFICITY.
RX PubMed=29300381; DOI=10.1038/gim.2017.227;
RA Khateb S., Kowalewski B., Bedoni N., Damme M., Pollack N., Saada A.,
RA Obolensky A., Ben-Yosef T., Gross M., Dierks T., Banin E., Rivolta C.,
RA Sharon D.;
RT "A homozygous founder missense variant in arylsulfatase G abolishes its
RT enzymatic activity causing atypical Usher syndrome in humans.";
RL Genet. Med. 20:1004-1012(2018).
RN [9]
RP VARIANTS SER-236; ARG-274; GLY-326; HIS-385; TRP-398; MET-444; LYS-481 AND
RP THR-493.
RX PubMed=25825126; DOI=10.1007/s00415-015-7718-3;
RA Nibbeling E., Schaake S., Tijssen M.A., Weissbach A., Groen J.L.,
RA Altenmueller E., Verbeek D.S., Lohmann K.;
RT "Accumulation of rare variants in the arylsulfatase G (ARSG) gene in task-
RT specific dystonia.";
RL J. Neurol. 262:1340-1343(2015).
CC -!- FUNCTION: Displays arylsulfatase activity at acidic pH towards
CC artificial substrates, such as p-nitrocatechol sulfate and also, but
CC with a lower activity towards p-nitrophenyl sulfate and 4-
CC methylumbelliferyl sulfate (PubMed:18283100, PubMed:29300381).
CC Catalyzes the hydrolysis of the 3-sulfate groups of the N-sulfo-D-
CC glucosamine 3-O-sulfate units of heparin (PubMed:22689975).
CC {ECO:0000269|PubMed:18283100, ECO:0000269|PubMed:22689975,
CC ECO:0000269|PubMed:29300381}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an aryl sulfate + H2O = a phenol + H(+) + sulfate;
CC Xref=Rhea:RHEA:17261, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16189, ChEBI:CHEBI:33853, ChEBI:CHEBI:140317; EC=3.1.6.1;
CC Evidence={ECO:0000269|PubMed:18283100, ECO:0000269|PubMed:29300381};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Hydrolysis of the 3-sulfate groups of the N-sulfo-D-
CC glucosamine 3-O-sulfate units of heparin.; EC=3.1.6.15;
CC Evidence={ECO:0000269|PubMed:22689975};
CC -!- COFACTOR:
CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108;
CC Evidence={ECO:0000250|UniProtKB:P15289};
CC Note=Binds 1 Ca(2+) ion per subunit. {ECO:0000250|UniProtKB:P15289};
CC -!- ACTIVITY REGULATION: Inhibited by phosphate. The phosphate forms a
CC covalent bond with the active site 3-oxoalanine.
CC {ECO:0000269|PubMed:18283100}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=4.2 mM for p-nitrocatechol sulfate {ECO:0000269|PubMed:18283100};
CC Vmax=63.5 umol/min/mg enzyme toward p-nitrocatechol sulfate
CC {ECO:0000269|PubMed:18283100};
CC pH dependence:
CC Optimum pH is 5.4. {ECO:0000269|PubMed:18283100};
CC Temperature dependence:
CC Most efficient at 45-50 degrees Celsius.
CC {ECO:0000269|PubMed:18283100};
CC -!- SUBCELLULAR LOCATION: Lysosome {ECO:0000269|PubMed:12461688,
CC ECO:0000269|PubMed:18283100}. Note=The 63-kDa precursor protein
CC localizes to pre-lysosomal compartments and tightly associates with
CC organelle membranes, most likely the endoplasmic reticulum. In
CC contrast, proteolytically processed fragments of 34-, 18- and 10-kDa
CC are found in lysosomal fractions and lose their membrane association.
CC {ECO:0000250|UniProtKB:Q3TYD4}.
CC -!- TISSUE SPECIFICITY: Widely expressed, with very low expression in
CC brain, lung, heart and skeletal muscle. {ECO:0000269|PubMed:12461688,
CC ECO:0000269|PubMed:18283100, ECO:0000269|PubMed:29300381}.
CC -!- PTM: N-glycosylated (PubMed:18283100). N-glycosylated with both high
CC mannose and complex type sugars (By similarity).
CC {ECO:0000250|UniProtKB:Q3TYD4, ECO:0000269|PubMed:18283100}.
CC -!- PTM: The conversion to 3-oxoalanine (also known as C-formylglycine,
CC FGly), of a serine or cysteine residue in prokaryotes and of a cysteine
CC residue in eukaryotes, is critical for catalytic activity.
CC {ECO:0000250|UniProtKB:P15289}.
CC -!- PTM: The 63-kDa precursor undergoes proteolytic processing in two
CC steps, yielding two fragments in the first step (apparent molecular
CC masses of 44 and 18 kDa) (PubMed:25135642). In the second step, the 44-
CC kDa fragment is processed further to the 34- and 10-kDa chains. The 10-
CC kDa chain is a cleavage product of the 44-kDa fragment but linked to
CC the 18-kDa chain through a disulfide bridge (PubMed:25135642).
CC {ECO:0000269|PubMed:25135642}.
CC -!- DISEASE: Usher syndrome 4 (USH4) [MIM:618144]: A form of Usher
CC syndrome, a genetically heterogeneous condition characterized by the
CC association of retinitis pigmentosa with sensorineural deafness. Age at
CC onset and differences in auditory and vestibular function distinguish
CC different types of Usher syndrome. USH4 is characterized by late onset
CC of retinitis pigmentosa and usually late-onset of progressive
CC sensorineural hearing loss without vestibular involvement. USH4
CC inheritance is autosomal recessive. {ECO:0000269|PubMed:29300381}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- SIMILARITY: Belongs to the sulfatase family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA76845.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AB023218; BAA76845.2; ALT_INIT; mRNA.
DR EMBL; AY358380; AAQ88746.1; -; mRNA.
DR EMBL; BC012375; AAH12375.1; -; mRNA.
DR CCDS; CCDS11676.1; -.
DR RefSeq; NP_001254656.1; NM_001267727.1.
DR RefSeq; NP_055775.2; NM_014960.4.
DR RefSeq; XP_005257227.1; XM_005257170.3.
DR RefSeq; XP_016879850.1; XM_017024361.1.
DR RefSeq; XP_016879851.1; XM_017024362.1.
DR RefSeq; XP_016879852.1; XM_017024363.1.
DR RefSeq; XP_016879853.1; XM_017024364.1.
DR RefSeq; XP_016879854.1; XM_017024365.1.
DR AlphaFoldDB; Q96EG1; -.
DR SMR; Q96EG1; -.
DR BioGRID; 116565; 91.
DR IntAct; Q96EG1; 20.
DR STRING; 9606.ENSP00000407193; -.
DR ChEMBL; CHEMBL2189124; -.
DR GlyGen; Q96EG1; 4 sites.
DR iPTMnet; Q96EG1; -.
DR PhosphoSitePlus; Q96EG1; -.
DR BioMuta; ARSG; -.
DR DMDM; 74731559; -.
DR EPD; Q96EG1; -.
DR MassIVE; Q96EG1; -.
DR PaxDb; Q96EG1; -.
DR PeptideAtlas; Q96EG1; -.
DR PRIDE; Q96EG1; -.
DR ProteomicsDB; 76405; -.
DR Antibodypedia; 19259; 189 antibodies from 23 providers.
DR DNASU; 22901; -.
DR Ensembl; ENST00000448504.6; ENSP00000407193.2; ENSG00000141337.13.
DR Ensembl; ENST00000621439.5; ENSP00000480910.1; ENSG00000141337.13.
DR GeneID; 22901; -.
DR KEGG; hsa:22901; -.
DR MANE-Select; ENST00000621439.5; ENSP00000480910.1; NM_001267727.2; NP_001254656.1.
DR UCSC; uc002jhc.3; human.
DR CTD; 22901; -.
DR DisGeNET; 22901; -.
DR GeneCards; ARSG; -.
DR HGNC; HGNC:24102; ARSG.
DR HPA; ENSG00000141337; Tissue enhanced (epididymis).
DR MalaCards; ARSG; -.
DR MIM; 610008; gene.
DR MIM; 618144; phenotype.
DR neXtProt; NX_Q96EG1; -.
DR OpenTargets; ENSG00000141337; -.
DR Orphanet; 231183; Usher syndrome type 3.
DR PharmGKB; PA143485307; -.
DR VEuPathDB; HostDB:ENSG00000141337; -.
DR eggNOG; KOG3867; Eukaryota.
DR GeneTree; ENSGT00940000159093; -.
DR HOGENOM; CLU_006332_13_6_1; -.
DR InParanoid; Q96EG1; -.
DR OMA; PFTGLWQ; -.
DR PhylomeDB; Q96EG1; -.
DR TreeFam; TF314186; -.
DR PathwayCommons; Q96EG1; -.
DR Reactome; R-HSA-1660662; Glycosphingolipid metabolism.
DR Reactome; R-HSA-1663150; The activation of arylsulfatases.
DR SABIO-RK; Q96EG1; -.
DR SignaLink; Q96EG1; -.
DR BioGRID-ORCS; 22901; 14 hits in 1069 CRISPR screens.
DR ChiTaRS; ARSG; human.
DR GenomeRNAi; 22901; -.
DR Pharos; Q96EG1; Tbio.
DR PRO; PR:Q96EG1; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; Q96EG1; protein.
DR Bgee; ENSG00000141337; Expressed in blood and 106 other tissues.
DR ExpressionAtlas; Q96EG1; baseline and differential.
DR Genevisible; Q96EG1; HS.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:HGNC-UCL.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0005764; C:lysosome; IDA:UniProtKB.
DR GO; GO:0004065; F:arylsulfatase activity; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0033889; F:N-sulfoglucosamine-3-sulfatase activity; IDA:UniProtKB.
DR GO; GO:0006790; P:sulfur compound metabolic process; IDA:UniProtKB.
DR Gene3D; 3.40.720.10; -; 1.
DR InterPro; IPR017850; Alkaline_phosphatase_core_sf.
DR InterPro; IPR024607; Sulfatase_CS.
DR InterPro; IPR000917; Sulfatase_N.
DR Pfam; PF00884; Sulfatase; 1.
DR SUPFAM; SSF53649; SSF53649; 1.
DR PROSITE; PS00523; SULFATASE_1; 1.
DR PROSITE; PS00149; SULFATASE_2; 1.
PE 1: Evidence at protein level;
KW Calcium; Deafness; Disease variant; Disulfide bond; Glycoprotein;
KW Hydrolase; Lysosome; Metal-binding; Reference proteome;
KW Retinitis pigmentosa; Signal; Usher syndrome.
FT SIGNAL 1..16
FT /evidence="ECO:0000255"
FT CHAIN 17..525
FT /note="Arylsulfatase G"
FT /id="PRO_0000042215"
FT ACT_SITE 84
FT /note="Nucleophile"
FT /evidence="ECO:0000269|PubMed:18283100"
FT ACT_SITE 139
FT /evidence="ECO:0000250|UniProtKB:P15289"
FT BINDING 44
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P15289"
FT BINDING 45
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P15289"
FT BINDING 84
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /note="via 3-oxoalanine"
FT /evidence="ECO:0000250|UniProtKB:P15289"
FT BINDING 137
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P15289"
FT BINDING 162
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P15289"
FT BINDING 251
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P15289"
FT BINDING 302
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P15289"
FT BINDING 303
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P15289"
FT MOD_RES 84
FT /note="3-oxoalanine (Cys)"
FT /evidence="ECO:0000269|PubMed:18283100"
FT CARBOHYD 117
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 215
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 356
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 497
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VARIANT 11
FT /note="A -> V (in dbSNP:rs8074806)"
FT /id="VAR_052511"
FT VARIANT 45
FT /note="D -> Y (in USH4; loss of sulfatase activity toward
FT p-nitrocatechol sulfate; loss of processing of the
FT precursor protein suggesting impaired transport to
FT lysosomes)"
FT /evidence="ECO:0000269|PubMed:29300381"
FT /id="VAR_081577"
FT VARIANT 236
FT /note="T -> S (in dbSNP:rs1558876)"
FT /evidence="ECO:0000269|PubMed:25825126"
FT /id="VAR_052512"
FT VARIANT 274
FT /note="W -> R (in dbSNP:rs1558878)"
FT /evidence="ECO:0000269|PubMed:25825126"
FT /id="VAR_052513"
FT VARIANT 326
FT /note="R -> G (in dbSNP:rs144503106)"
FT /evidence="ECO:0000269|PubMed:25825126"
FT /id="VAR_074038"
FT VARIANT 385
FT /note="R -> H (in dbSNP:rs9972951)"
FT /evidence="ECO:0000269|PubMed:25825126"
FT /id="VAR_052514"
FT VARIANT 398
FT /note="R -> W (in dbSNP:rs11657051)"
FT /evidence="ECO:0000269|PubMed:25825126"
FT /id="VAR_074039"
FT VARIANT 444
FT /note="T -> M (in dbSNP:rs62000424)"
FT /evidence="ECO:0000269|PubMed:25825126"
FT /id="VAR_074040"
FT VARIANT 481
FT /note="E -> K (in dbSNP:rs370852507)"
FT /evidence="ECO:0000269|PubMed:25825126"
FT /id="VAR_074041"
FT VARIANT 493
FT /note="I -> T (in dbSNP:rs61999318)"
FT /evidence="ECO:0000269|PubMed:25825126"
FT /id="VAR_074042"
FT MUTAGEN 84
FT /note="C->A: No sulfatase activity."
FT /evidence="ECO:0000269|PubMed:18283100"
FT MUTAGEN 501
FT /note="A->P: Decrease of sulfatase activity."
FT /evidence="ECO:0000269|PubMed:18283100"
FT CONFLICT 444..445
FT /note="TG -> MV (in Ref. 2; AAQ88746)"
FT /evidence="ECO:0000305"
FT CONFLICT 501
FT /note="A -> P (in Ref. 1; BAA76845)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 525 AA; 57061 MW; ADAB673A02B25754 CRC64;
MGWLFLKVLL AGVSFSGFLY PLVDFCISGK TRGQKPNFVI ILADDMGWGD LGANWAETKD
TANLDKMASE GMRFVDFHAA ASTCSPSRAS LLTGRLGLRN GVTRNFAVTS VGGLPLNETT
LAEVLQQAGY VTGIIGKWHL GHHGSYHPNF RGFDYYFGIP YSHDMGCTDT PGYNHPPCPA
CPQGDGPSRN LQRDCYTDVA LPLYENLNIV EQPVNLSSLA QKYAEKATQF IQRASTSGRP
FLLYVALAHM HVPLPVTQLP AAPRGRSLYG AGLWEMDSLV GQIKDKVDHT VKENTFLWFT
GDNGPWAQKC ELAGSVGPFT GFWQTRQGGS PAKQTTWEGG HRVPALAYWP GRVPVNVTST
ALLSVLDIFP TVVALAQASL PQGRRFDGVD VSEVLFGRSQ PGHRVLFHPN SGAAGEFGAL
QTVRLERYKA FYITGGARAC DGSTGPELQH KFPLIFNLED DTAEAVPLER GGAEYQAVLP
EVRKVLADVL QDIANDNISS ADYTQDPSVT PCCNPYQIAC RCQAA
