ID HYAS3_MOUSE Reviewed; 554 AA. AC O08650; Q8CEB9; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 27-JUL-2011, sequence version 2. DT 27-MAR-2024, entry version 161. DE RecName: Full=Hyaluronan synthase 3; DE EC=2.4.1.212 {ECO:0000269|PubMed:10455188, ECO:0000269|PubMed:16014622}; DE AltName: Full=Hyaluronate synthase 3; DE AltName: Full=Hyaluronic acid synthase 3; DE Short=HA synthase 3; GN Name=Has3; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND DEVELOPMENTAL STAGE. RC STRAIN=129/SvJ, and C57BL/6J; RX PubMed=9083017; DOI=10.1074/jbc.272.14.8957; RA Spicer A.P., Olson J.S., McDonald J.A.; RT "Molecular cloning and characterization of a cDNA encoding the third RT putative mammalian hyaluronan synthase."; RL J. Biol. Chem. 272:8957-8961(1997). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=C57BL/6J; TISSUE=Skin; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; 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 FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND RP SUBCELLULAR LOCATION. RX PubMed=10455188; DOI=10.1074/jbc.274.35.25085; RA Itano N., Sawai T., Yoshida M., Lenas P., Yamada Y., Imagawa M., RA Shinomura T., Hamaguchi M., Yoshida Y., Ohnuki Y., Miyauchi S., RA Spicer A.P., McDonald J.A., Kimata K.; RT "Three isoforms of mammalian hyaluronan synthases have distinct enzymatic RT properties."; RL J. Biol. Chem. 274:25085-25092(1999). RN [5] RP SUBCELLULAR LOCATION, FUCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF RP ASP-216. RX PubMed=16014622; DOI=10.1074/jbc.m504736200; RA Rilla K., Siiskonen H., Spicer A.P., Hyttinen J.M., Tammi M.I., Tammi R.H.; RT "Plasma membrane residence of hyaluronan synthase is coupled to its RT enzymatic activity."; RL J. Biol. Chem. 280:31890-31897(2005). RN [6] RP DISRUPTION PHENOTYPE. RX PubMed=24790187; DOI=10.1523/jneurosci.3458-13.2014; RA Arranz A.M., Perkins K.L., Irie F., Lewis D.P., Hrabe J., Xiao F., RA Itano N., Kimata K., Hrabetova S., Yamaguchi Y.; RT "Hyaluronan deficiency due to Has3 knock-out causes altered neuronal RT activity and seizures via reduction in brain extracellular space."; RL J. Neurosci. 34:6164-6176(2014). CC -!- FUNCTION: Catalyzes the addition of GlcNAc or GlcUA monosaccharides to CC the nascent hyaluronan polymer. Therefore, it is essential to CC hyaluronan synthesis a major component of most extracellular matrices CC that has a structural role in tissues architectures and regulates cell CC adhesion, migration and differentiation. This is one of three CC isoenzymes responsible for cellular hyaluronan synthesis. CC {ECO:0000269|PubMed:10455188, ECO:0000269|PubMed:16014622}. CC -!- CATALYTIC ACTIVITY: CC Reaction=[hyaluronan](n) + UDP-N-acetyl-alpha-D-glucosamine = H(+) + N- CC acetyl-beta-D-glucosaminyl-(1->4)-[hyaluronan](n) + UDP; CC Xref=Rhea:RHEA:20465, Rhea:RHEA-COMP:12583, Rhea:RHEA-COMP:12585, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57705, ChEBI:CHEBI:58223, CC ChEBI:CHEBI:132153, ChEBI:CHEBI:132154; EC=2.4.1.212; CC Evidence={ECO:0000269|PubMed:10455188, ECO:0000269|PubMed:16014622}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:20466; CC Evidence={ECO:0000269|PubMed:10455188}; CC -!- CATALYTIC ACTIVITY: CC Reaction=N-acetyl-beta-D-glucosaminyl-(1->4)-[hyaluronan](n) + UDP- CC alpha-D-glucuronate = [hyaluronan](n+1) + H(+) + UDP; CC Xref=Rhea:RHEA:12528, Rhea:RHEA-COMP:12585, Rhea:RHEA-COMP:12587, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:58052, ChEBI:CHEBI:58223, CC ChEBI:CHEBI:132153, ChEBI:CHEBI:132154; EC=2.4.1.212; CC Evidence={ECO:0000269|PubMed:10455188, ECO:0000269|PubMed:16014622}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:12529; CC Evidence={ECO:0000269|PubMed:10455188}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=0.2 mM for UDP-Glc-NAc (at pH 7.1 and 37 degrees Celsius, in the CC presence of 15 mM MgCl2) {ECO:0000269|PubMed:10455188}; CC KM=0.3 mM for UDP-Glc-UA (at pH 7.1 and 37 degrees Celsius, in the CC presence of 15 mM MgCl2) {ECO:0000269|PubMed:10455188}; CC -!- PATHWAY: Glycan biosynthesis; hyaluronan biosynthesis. CC {ECO:0000269|PubMed:10455188, ECO:0000269|PubMed:16014622}. CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:10455188, CC ECO:0000269|PubMed:16014622}; Multi-pass membrane protein CC {ECO:0000255}. Golgi apparatus membrane {ECO:0000269|PubMed:16014622}; CC Multi-pass membrane protein {ECO:0000255}. Golgi apparatus, trans-Golgi CC network membrane {ECO:0000269|PubMed:16014622}; Multi-pass membrane CC protein {ECO:0000255}. Cytoplasmic vesicle CC {ECO:0000269|PubMed:16014622}. Note=Travels through endoplasmic CC reticulum (ER), Golgi, plasma membrane, and endocytic vesicles CC (PubMed:16014622). Actives only when present in plasma membrane CC (PubMed:16014622). O-GlcNAcylation controls its membrane localization CC (By similarity). A rapid recycling of HAS3 between plasma membrane and CC endosomes is controlled by the cytosolic levels of UDP-GlcUA and UDP- CC GlcNAc (By similarity). {ECO:0000250|UniProtKB:O00219, CC ECO:0000269|PubMed:16014622}. CC -!- DEVELOPMENTAL STAGE: Expressed at 17.5 dpc. CC {ECO:0000269|PubMed:9083017}. CC -!- PTM: O-GlcNAcylation increases the hyaluronan synthase activity, HAS3 CC stability and its plasma membrane residence. The concentration of UDP- CC GlcNAc controls the level of O-GlcNAc modification. CC {ECO:0000250|UniProtKB:O00219}. CC -!- DISRUPTION PHENOTYPE: Deficient mice are viable and fertile however CC absence of HAS3 increases the excitability of neural networks and CC drives the formation of epileptic seizures. CC {ECO:0000269|PubMed:24790187}. CC -!- SIMILARITY: Belongs to the NodC/HAS family. {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; U86408; AAC53128.1; -; mRNA. DR EMBL; AK028582; BAC26017.1; -; mRNA. DR EMBL; BC138152; AAI38153.1; -; mRNA. DR CCDS; CCDS22640.1; -. DR RefSeq; NP_001317977.1; NM_001331048.1. DR RefSeq; NP_032243.2; NM_008217.4. DR RefSeq; XP_006530763.1; XM_006530700.3. DR RefSeq; XP_006530764.1; XM_006530701.2. DR AlphaFoldDB; O08650; -. DR SMR; O08650; -. DR STRING; 10090.ENSMUSP00000034385; -. DR CAZy; GT2; Glycosyltransferase Family 2. DR GlyCosmos; O08650; 1 site, No reported glycans. DR GlyGen; O08650; 1 site. DR PhosphoSitePlus; O08650; -. DR PaxDb; 10090-ENSMUSP00000034385; -. DR ProteomicsDB; 273063; -. DR Antibodypedia; 29818; 300 antibodies from 32 providers. DR DNASU; 15118; -. DR Ensembl; ENSMUST00000034385.12; ENSMUSP00000034385.6; ENSMUSG00000031910.15. DR Ensembl; ENSMUST00000176144.8; ENSMUSP00000135303.2; ENSMUSG00000031910.15. DR GeneID; 15118; -. DR KEGG; mmu:15118; -. DR UCSC; uc009ngn.2; mouse. DR AGR; MGI:109599; -. DR CTD; 3038; -. DR MGI; MGI:109599; Has3. DR VEuPathDB; HostDB:ENSMUSG00000031910; -. DR eggNOG; KOG2571; Eukaryota. DR GeneTree; ENSGT00390000010337; -. DR HOGENOM; CLU_029695_3_0_1; -. DR InParanoid; O08650; -. DR OMA; RWARSTY; -. DR OrthoDB; 1361850at2759; -. DR PhylomeDB; O08650; -. DR TreeFam; TF332506; -. DR BRENDA; 2.4.1.212; 3474. DR Reactome; R-MMU-2142850; Hyaluronan biosynthesis and export. DR SABIO-RK; O08650; -. DR UniPathway; UPA00341; -. DR BioGRID-ORCS; 15118; 2 hits in 76 CRISPR screens. DR PRO; PR:O08650; -. DR Proteomes; UP000000589; Chromosome 8. DR RNAct; O08650; Protein. DR Bgee; ENSMUSG00000031910; Expressed in inner dental epithelium and 108 other cell types or tissues. DR ExpressionAtlas; O08650; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:CACAO. DR GO; GO:0031410; C:cytoplasmic vesicle; IEA:UniProtKB-KW. DR GO; GO:0005794; C:Golgi apparatus; ISO:MGI. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0036117; C:hyaluranon cable; ISO:MGI. DR GO; GO:0005634; C:nucleus; IDA:CACAO. DR GO; GO:0005886; C:plasma membrane; IDA:MGI. DR GO; GO:0050501; F:hyaluronan synthase activity; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; ISO:MGI. DR GO; GO:0085029; P:extracellular matrix assembly; IDA:UniProtKB. DR GO; GO:0045226; P:extracellular polysaccharide biosynthetic process; IDA:UniProtKB. DR GO; GO:0030213; P:hyaluronan biosynthetic process; IDA:MGI. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; ISO:MGI. DR GO; GO:1900106; P:positive regulation of hyaluranon cable assembly; ISO:MGI. DR CDD; cd06434; GT2_HAS; 1. DR InterPro; IPR029044; Nucleotide-diphossugar_trans. DR PANTHER; PTHR22913; HYALURONAN SYNTHASE; 1. DR PANTHER; PTHR22913:SF6; HYALURONAN SYNTHASE 3; 1. DR Pfam; PF13641; Glyco_tranf_2_3; 1. DR SUPFAM; SSF53448; Nucleotide-diphospho-sugar transferases; 1. DR Genevisible; O08650; MM. PE 1: Evidence at protein level; KW Cell membrane; Cytoplasmic vesicle; Glycoprotein; Glycosyltransferase; KW Golgi apparatus; Membrane; Reference proteome; Transferase; Transmembrane; KW Transmembrane helix. FT CHAIN 1..554 FT /note="Hyaluronan synthase 3" FT /id="PRO_0000197179" FT TOPO_DOM 1..15 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 16..36 FT /note="Helical; Name=1" FT /evidence="ECO:0000255" FT TOPO_DOM 37..44 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 45..65 FT /note="Helical; Name=2" FT /evidence="ECO:0000255" FT TOPO_DOM 66..378 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 379..399 FT /note="Helical; Name=3" FT /evidence="ECO:0000255" FT TOPO_DOM 400..409 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 410..430 FT /note="Helical; Name=4" FT /evidence="ECO:0000255" FT TOPO_DOM 431..441 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 442..462 FT /note="Helical; Name=5" FT /evidence="ECO:0000255" FT TOPO_DOM 463..474 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 475..495 FT /note="Helical; Name=6" FT /evidence="ECO:0000255" FT TOPO_DOM 496..516 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 517..537 FT /note="Helical; Name=7" FT /evidence="ECO:0000255" FT TOPO_DOM 538..554 FT /note="Extracellular" FT /evidence="ECO:0000255" FT CARBOHYD 463 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT MUTAGEN 216 FT /note="D->A: Not detectable on the plasma membrane. FT Abolishes hyaluronan synthase activity." FT /evidence="ECO:0000269|PubMed:16014622" FT CONFLICT 85 FT /note="P -> S (in Ref. 1; AAC53128)" FT /evidence="ECO:0000305" SQ SEQUENCE 554 AA; 63349 MW; BFFF239C901251DE CRC64; MPVQLTTALR VVGTSLFALV VLGGILAAYV TGYQFIHTEK HYLSFGLYGA ILGLHLLIQS LFAFLEHRRM RRAGRPLKLH CSQRPRSVAL CIAAYQEDPE YLRKCLRSAQ RIAFPNLKVV MVVDGNRQED TYMLDIFHEV LGGTEQAGFF VWRSNFHEAG EGETEASLQE GMERVRAVVW ASTFSCIMQK WGGKREVMYT AFKALGNSVD YIQVCDSDTV LDPACTIEML RVLEEDPQVG GVGGDVQILN KYDSWISFLS SVRYWMAFNV ERACQSYFGC VQCISGPLGM YRNSLLQQFL EDWYHQKFLG SKCSFGDDRH LTNRVLSLGY RTKYTARSKC LTETPTRYLR WLNQQTRWSK SYFREWLYNS LWFHKHHLWM TYESVVTGFF PFFLIATVIQ LFYRGRIWNI LLFLLTVQLV GIIKATYACF LRGNAEMIFM SLYSLLYMSS LLPAKIFAIA TINKSGWGTS GRKTIVVNFI GLIPVSIWVA VLLGGLAYTA YCQDLFSETE LAFLVSGAIL YGCYWVALLM LYLAIIARRC GKKPEQYSLA FAEV //