ID   HS3S6_HUMAN             Reviewed;         342 AA.
AC   Q96QI5; Q96RX7;
DT   15-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT   15-MAR-2005, sequence version 2.
DT   27-NOV-2024, entry version 161.
DE   RecName: Full=Heparan sulfate glucosamine 3-O-sulfotransferase 6;
DE            EC=2.8.2.23;
DE   AltName: Full=Heparan sulfate D-glucosaminyl 3-O-sulfotransferase 6;
DE            Short=3-OST-6;
DE            Short=Heparan sulfate 3-O-sulfotransferase 6;
DE            Short=h3-OST-6;
GN   Name=HS3ST6; Synonyms=HS3ST5;
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=11157797; DOI=10.1093/hmg/10.4.339;
RA   Daniels R.J., Peden J.F., Lloyd C., Horsley S.W., Clark K., Tufarelli C.,
RA   Kearney L., Buckle V.J., Doggett N.A., Flint J., Higgs D.R.;
RT   "Sequence, structure and pathology of the fully annotated terminal 2 Mb of
RT   the short arm of human chromosome 16.";
RL   Hum. Mol. Genet. 10:339-352(2001).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15616553; DOI=10.1038/nature03187;
RA   Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G.,
RA   Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E.,
RA   Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M.,
RA   Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C.,
RA   Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M.,
RA   Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M.,
RA   Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D.,
RA   Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L.,
RA   Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E.,
RA   Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H.,
RA   Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y.,
RA   Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA   Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA   Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S.,
RA   Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A.,
RA   Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M.,
RA   Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H.,
RA   Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A.,
RA   Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J.,
RA   DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J.,
RA   Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M.,
RA   Myers R.M., Rubin E.M., Pennacchio L.A.;
RT   "The sequence and analysis of duplication-rich human chromosome 16.";
RL   Nature 432:988-994(2004).
RN   [3]
RP   FUNCTION IN HSV-1 ENTRY.
RX   PubMed=15303968; DOI=10.1042/bj20040908;
RA   Xu D., Tiwari V., Xia G., Clement C., Shukla D., Liu J.;
RT   "Characterization of heparan sulphate 3-O-sulphotransferase isoform 6 and
RT   its role in assisting the entry of herpes simplex virus type 1.";
RL   Biochem. J. 385:451-459(2005).
RN   [4]
RP   VARIANT HAE8 SER-144, AND INVOLVEMENT IN HAE8.
RX   PubMed=33508266; DOI=10.1016/j.jaci.2021.01.011;
RA   Bork K., Wulff K., Moehl B.S., Steinmueller-Magin L., Witzke G., Hardt J.,
RA   Meinke P.;
RT   "Novel hereditary angioedema linked with a heparan sulfate 3-O-
RT   sulfotransferase 6 gene mutation.";
RL   J. Allergy Clin. Immunol. 148:1041-1048(2021).
CC   -!- FUNCTION: Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate
CC       (PAPS) to catalyze the transfer of a sulfo group to heparan sulfate.
CC       The substrate-specific O-sulfation generates an enzyme-modified heparan
CC       sulfate which acts as a binding receptor to Herpes Simplex Virus-1
CC       (HSV-1) and permits its entry. Unlike 3-OST-1, does not convert non-
CC       anticoagulant heparan sulfate to anticoagulant heparan sulfate.
CC       {ECO:0000269|PubMed:15303968}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=alpha-D-glucosaminyl-[heparan sulfate](n) + 3'-phosphoadenylyl
CC         sulfate = 3-sulfo-alpha-D-glucosaminyl-[heparan sulfate](n) +
CC         adenosine 3',5'-bisphosphate + H(+); Xref=Rhea:RHEA:15461, Rhea:RHEA-
CC         COMP:9830, Rhea:RHEA-COMP:9831, ChEBI:CHEBI:15378, ChEBI:CHEBI:58339,
CC         ChEBI:CHEBI:58343, ChEBI:CHEBI:58388, ChEBI:CHEBI:70975; EC=2.8.2.23;
CC   -!- SUBCELLULAR LOCATION: Golgi apparatus membrane {ECO:0000305}; Single-
CC       pass type II membrane protein {ECO:0000305}.
CC   -!- DISEASE: Angioedema, hereditary, 8 (HAE8) [MIM:619367]: A form of
CC       angioedema, a disorder characterized by episodic local swelling
CC       involving subcutaneous or submucous tissue of the upper respiratory and
CC       gastrointestinal tracts, face, extremities, and genitalia. HAE8
CC       inheritance is autosomal dominant. {ECO:0000269|PubMed:33508266}.
CC       Note=The disease may be caused by variants affecting the gene
CC       represented in this entry.
CC   -!- SIMILARITY: Belongs to the sulfotransferase 1 family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAK61299.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; AE006640; AAK61299.1; ALT_INIT; Genomic_DNA.
DR   EMBL; AL031723; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   CCDS; CCDS45381.2; -.
DR   RefSeq; NP_001009606.3; NM_001009606.3.
DR   AlphaFoldDB; Q96QI5; -.
DR   SMR; Q96QI5; -.
DR   BioGRID; 122239; 9.
DR   IntAct; Q96QI5; 4.
DR   STRING; 9606.ENSP00000416741; -.
DR   GlyCosmos; Q96QI5; 1 site, No reported glycans.
DR   GlyGen; Q96QI5; 1 site.
DR   iPTMnet; Q96QI5; -.
DR   PhosphoSitePlus; Q96QI5; -.
DR   BioMuta; HS3ST6; -.
DR   DMDM; 61214397; -.
DR   MassIVE; Q96QI5; -.
DR   PaxDb; 9606-ENSP00000416741; -.
DR   PeptideAtlas; Q96QI5; -.
DR   ProteomicsDB; 77881; -.
DR   Antibodypedia; 23316; 25 antibodies from 14 providers.
DR   DNASU; 64711; -.
DR   Ensembl; ENST00000293937.5; ENSP00000293937.3; ENSG00000276333.2.
DR   Ensembl; ENST00000454677.3; ENSP00000416741.3; ENSG00000162040.7.
DR   GeneID; 64711; -.
DR   KEGG; hsa:64711; -.
DR   MANE-Select; ENST00000454677.3; ENSP00000416741.3; NM_001009606.4; NP_001009606.3.
DR   UCSC; uc032epu.2; human.
DR   AGR; HGNC:14178; -.
DR   CTD; 64711; -.
DR   DisGeNET; 64711; -.
DR   GeneCards; HS3ST6; -.
DR   HGNC; HGNC:14178; HS3ST6.
DR   HPA; ENSG00000162040; Tissue enriched (skin).
DR   MalaCards; HS3ST6; -.
DR   MIM; 619210; gene.
DR   MIM; 619367; phenotype.
DR   neXtProt; NX_Q96QI5; -.
DR   OpenTargets; ENSG00000162040; -.
DR   Orphanet; 599418; Hereditary angioedema with normal C1Inh not related to F12 or PLG variant.
DR   VEuPathDB; HostDB:ENSG00000162040; -.
DR   eggNOG; KOG3704; Eukaryota.
DR   GeneTree; ENSGT00940000154768; -.
DR   InParanoid; Q96QI5; -.
DR   OMA; RVCTMNC; -.
DR   OrthoDB; 10019at2759; -.
DR   PhylomeDB; Q96QI5; -.
DR   BRENDA; 2.8.2.23; 2681.
DR   PathwayCommons; Q96QI5; -.
DR   Reactome; R-HSA-2022928; HS-GAG biosynthesis.
DR   BioGRID-ORCS; 64711; 23 hits in 1112 CRISPR screens.
DR   GenomeRNAi; 64711; -.
DR   Pharos; Q96QI5; Tdark.
DR   PRO; PR:Q96QI5; -.
DR   Proteomes; UP000005640; Chromosome 16.
DR   RNAct; Q96QI5; protein.
DR   Bgee; ENSG00000162040; Expressed in skin of leg and 46 other cell types or tissues.
DR   GO; GO:0000139; C:Golgi membrane; TAS:Reactome.
DR   GO; GO:0008467; F:[heparan sulfate]-glucosamine 3-sulfotransferase 1 activity; ISS:UniProtKB.
DR   GO; GO:0001835; P:blastocyst hatching; IEA:Ensembl.
DR   GO; GO:0015015; P:heparan sulfate proteoglycan biosynthetic process, enzymatic modification; TAS:Reactome.
DR   FunFam; 3.40.50.300:FF:000194; Sulfotransferase; 1.
DR   Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 1.
DR   InterPro; IPR037359; NST/OST.
DR   InterPro; IPR027417; P-loop_NTPase.
DR   InterPro; IPR000863; Sulfotransferase_dom.
DR   PANTHER; PTHR10605:SF65; HEPARAN SULFATE GLUCOSAMINE 3-O-SULFOTRANSFERASE 6; 1.
DR   PANTHER; PTHR10605; HEPARAN SULFATE SULFOTRANSFERASE; 1.
DR   Pfam; PF00685; Sulfotransfer_1; 1.
DR   SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1.
PE   1: Evidence at protein level;
KW   Disulfide bond; Glycoprotein; Golgi apparatus; Membrane;
KW   Proteomics identification; Reference proteome; Signal-anchor; Transferase;
KW   Transmembrane; Transmembrane helix.
FT   CHAIN           1..342
FT                   /note="Heparan sulfate glucosamine 3-O-sulfotransferase 6"
FT                   /id="PRO_0000085224"
FT   TOPO_DOM        1..31
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        32..49
FT                   /note="Helical; Signal-anchor for type II membrane protein"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        50..342
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255"
FT   REGION          1..21
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          55..85
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   BINDING         100..104
FT                   /ligand="3'-phosphoadenylyl sulfate"
FT                   /ligand_id="ChEBI:CHEBI:58339"
FT                   /evidence="ECO:0000250"
FT   BINDING         122..128
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
FT   BINDING         153..156
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
FT   BINDING         181
FT                   /ligand="3'-phosphoadenylyl sulfate"
FT                   /ligand_id="ChEBI:CHEBI:58339"
FT                   /evidence="ECO:0000250"
FT   BINDING         189
FT                   /ligand="3'-phosphoadenylyl sulfate"
FT                   /ligand_id="ChEBI:CHEBI:58339"
FT                   /evidence="ECO:0000250"
FT   BINDING         220..221
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
FT   BINDING         305..309
FT                   /ligand="3'-phosphoadenylyl sulfate"
FT                   /ligand_id="ChEBI:CHEBI:58339"
FT                   /evidence="ECO:0000250"
FT   CARBOHYD        281
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        288..300
FT                   /evidence="ECO:0000250"
FT   VARIANT         144
FT                   /note="T -> S (in HAE8; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:33508266"
FT                   /id="VAR_085820"
FT   CONFLICT        192
FT                   /note="A -> T (in Ref. 1)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        316
FT                   /note="L -> V (in Ref. 1)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   342 AA;  37186 MW;  3CB8FFD4AFA7F9DC CRC64;
     MAGSGGLGGG AGGGQGAGAG QGAALRASRA PMLLVALVLG AYCLCALPGR CPPAARAPAP
     APAPSEPSSS VHRPGAPGLP LASGPGRRRF PQALIVGVKK GGTRALLEFL RLHPDVRALG
     SEPHFFDRCY ERGLAWYRSL MPRTLDGQIT MEKTPSYFVT REAPRRIHAM SPDTKLIVVV
     RNPVTRAISD YAQTLSKTPG LPSFRALAFR HGLGPVDTAW SAVRIGLYAQ HLDHWLRYFP
     LSHFLFVSGE RLVSDPAGEV GRVQDFLGLK RVVTDKHFYF NATKGFPCLK KAQGGSRPRC
     LGKSKGRPHP RVPQALVRRL QEFYRPFNRR FYQMTGQDFG WG
//