ID PAPS2_HUMAN Reviewed; 614 AA. AC O95340; Q9BZL2; Q9P0G6; Q9UHM1; Q9UKD3; Q9UP30; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 16-APR-2002, sequence version 2. DT 27-MAY-2015, entry version 148. DE RecName: Full=Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 2; DE Short=PAPS synthase 2; DE Short=PAPSS 2; DE AltName: Full=Sulfurylase kinase 2; DE Short=SK 2; DE Short=SK2; DE Includes: DE RecName: Full=Sulfate adenylyltransferase; DE EC=2.7.7.4; DE AltName: Full=ATP-sulfurylase; DE AltName: Full=Sulfate adenylate transferase; DE Short=SAT; DE Includes: DE RecName: Full=Adenylyl-sulfate kinase; DE EC=2.7.1.25; DE AltName: Full=3'-phosphoadenosine-5'-phosphosulfate synthase; DE AltName: Full=APS kinase; DE AltName: Full=Adenosine-5'-phosphosulfate 3'-phosphotransferase; DE AltName: Full=Adenylylsulfate 3'-phosphotransferase; GN Name=PAPSS2; Synonyms=ATPSK2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A). RC TISSUE=Fetal cartilage; RX PubMed=9771708; DOI=10.1038/2458; RA ul Haque M.F., King L.M., Krakow D., Cantor R.M., Rusiniak M.E., RA Swank R.T., Superti-Furga A., Haque S., Abbas H., Ahmad W., Ahmad M., RA Cohn D.H.; RT "Mutations in orthologous genes in human spondyloepimetaphyseal RT dysplasia and the brachymorphic mouse."; RL Nat. Genet. 20:157-162(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A). RA Franzon V.L., Gibson M.A., Hatzinikolas G., Cleary E.G., Woolatt E., RA Sutherland G.R.; RL Submitted (JUN-1998) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A). RA Fuda H., Shimizu C., Strott C.A.; RT "Human bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase: RT differential expression of isoforms and effect of polymorphisms on RT activity."; RL Submitted (OCT-2000) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM A). RX PubMed=10679223; DOI=10.1006/bbrc.2000.2123; RA Xu Z.-H., Otterness D.M., Freimuth R.R., Carlini E.J., Wood T.C., RA Mitchell S., Moon E., Kim U.-J., Xu J.-P., Siciliano M.J., RA Weinshilboum R.M.; RT "Human 3'-phosphoadenosine 5'-phosphosulfate synthetase 1 (PAPSS1) and RT PAPSS2: gene cloning, characterization and chromosomal localization."; RL Biochem. Biophys. Res. Commun. 268:437-444(2000). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM B). RC TISSUE=Liver; RX PubMed=10559207; DOI=10.1074/jbc.274.47.33306; RA Kurima K., Singh B., Schwartz N.B.; RT "Genomic organization of the mouse and human genes encoding the ATP RT sulfurylase/adenosine 5'-phosphosulfate kinase isoform SK2."; RL J. Biol. Chem. 274:33306-33312(1999). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM B). RA Venkatachalam K.V., Fuda H., Strott C.A.; RT "3'-phosphoadenosine 5'-phosphosulfate synthase 2b isoform."; RL Submitted (JAN-2001) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A). RC TISSUE=Colon; 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP INVOLVEMENT IN SEMD-PA. RX PubMed=9714015; RX DOI=10.1002/(SICI)1096-8628(19980806)78:5<468::AID-AJMG13>3.0.CO;2-D; RA Ahmad M., Haque M.F., Ahmad W., Abbas H., Haque S., Krakow D., RA Rimoin D.L., Lachman R.S., Cohn D.H.; RT "Distinct, autosomal recessive form of spondyloepimetaphyseal RT dysplasia segregating in an inbred Pakistani kindred."; RL Am. J. Med. Genet. 78:468-473(1998). RN [9] RP TISSUE SPECIFICITY, VARIANT SEMD-PA ARG-48, AND CHARACTERIZATION OF RP VARIANT SEMD-PA ARG-48. RX PubMed=19474428; DOI=10.1056/NEJMoa0810489; RA Noordam C., Dhir V., McNelis J.C., Schlereth F., Hanley N.A., RA Krone N., Smeitink J.A., Smeets R., Sweep F.C., RA Claahsen-van der Grinten H.L., Arlt W.; RT "Inactivating PAPSS2 mutations in a patient with premature pubarche."; RL N. Engl. J. Med. 360:2310-2318(2009). RN [10] 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., RA Buerckstuemmer T., 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 [11] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., RA Wang L., Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human RT liver phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [12] RP VARIANTS LYS-10; LEU-281; MET-291 AND LYS-432, AND CHARACTERIZATION OF RP VARIANTS LYS-10 AND MET-291. RX PubMed=11773860; DOI=10.1097/00008571-200201000-00003; RA Xu Z.-H., Freimuth R.R., Eckloff B., Wieben E., Weinshilboum R.M.; RT "Human 3'-phosphoadenosine 5'-phosphosulfate synthetase 2 (PAPSS2) RT pharmacogenetics: gene resequencing, genetic polymorphisms and RT functional characterization of variant allozymes."; RL Pharmacogenetics 12:11-21(2002). RN [13] RP INVOLVEMENT IN SEMD-PA. RX PubMed=23633440; DOI=10.1002/ajmg.a.35906; RA Tueysuez B., Yilmaz S., Guel E., Kolb L., Bilguvar K., Evliyaoglu O., RA Guenel M.; RT "Spondyloepimetaphyseal dysplasia Pakistani type: expansion of the RT phenotype."; RL Am. J. Med. Genet. A 161A:1300-1308(2013). RN [14] RP VARIANTS SEMD-PA TYR-43 AND GLN-76, CHARACTERIZATION OF VARIANTS RP SEMD-PA TYR-43 AND GLN-76, VARIANT LYS-183, AND CHARACTERIZATION OF RP VARIANT LYS-183. RX PubMed=23824674; DOI=10.1002/humu.22377; RA Iida A., Simsek-Kiper P.O., Mizumoto S., Hoshino T., Elcioglu N., RA Horemuzova E., Geiberger S., Yesil G., Kayserili H., Utine G.E., RA Boduroglu K., Watanabe S., Ohashi H., Alanay Y., Sugahara K., RA Nishimura G., Ikegawa S.; RT "Clinical and radiographic features of the autosomal recessive form of RT brachyolmia caused by PAPSS2 mutations."; RL Hum. Mutat. 34:1381-1386(2013). RN [15] RP VARIANT SEMD-PA ASP-270, AND CHARACTERIZATION OF VARIANTS SEMD-PA RP ARG-48 AND ASP-270. RX PubMed=25594860; DOI=10.1210/jc.2014-3556; RA Oostdijk W., Idkowiak J., Mueller J.W., House P.J., Taylor A.E., RA O'Reilly M.W., Hughes B.A., de Vries M.C., Kant S.G., Santen G.W., RA Verkerk A.J., Uitterlinden A.G., Wit J.M., Losekoot M., Arlt W.; RT "PAPSS2 deficiency causes androgen excess via impaired DHEA sulfation RT - in vitro and in vivo studies in a family harboring two novel PAPSS2 RT mutations."; RL J. Clin. Endocrinol. Metab. 2015:JC20143556-JC20143556(2015). CC -!- FUNCTION: Bifunctional enzyme with both ATP sulfurylase and APS CC kinase activity, which mediates two steps in the sulfate CC activation pathway. The first step is the transfer of a sulfate CC group to ATP to yield adenosine 5'-phosphosulfate (APS), and the CC second step is the transfer of a phosphate group from ATP to APS CC yielding 3'-phosphoadenylylsulfate (PAPS: activated sulfate donor CC used by sulfotransferase). In mammals, PAPS is the sole source of CC sulfate; APS appears to be only an intermediate in the sulfate- CC activation pathway. May have a important role in skeletogenesis CC during postnatal growth (By similarity). {ECO:0000250}. CC -!- CATALYTIC ACTIVITY: ATP + sulfate = diphosphate + adenylyl CC sulfate. CC -!- CATALYTIC ACTIVITY: ATP + adenylyl sulfate = ADP + 3'- CC phosphoadenylyl sulfate. CC -!- PATHWAY: Sulfur metabolism; sulfate assimilation. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=A; CC IsoId=O95340-1; Sequence=Displayed; CC Name=B; CC IsoId=O95340-2; Sequence=VSP_001259; CC -!- TISSUE SPECIFICITY: Expressed in cartilage and adrenal gland. CC {ECO:0000269|PubMed:19474428}. CC -!- DISEASE: Spondyloepimetaphyseal dysplasia Pakistani type (SEMD-PA) CC [MIM:612847]: A bone disease characterized by epiphyseal dysplasia CC with mild metaphyseal abnormalities. Clinical features include CC short stature evidenced at birth, short and bowed lower limbs, CC mild brachydactyly, kyphoscoliosis, abnormal gait, enlarged knee CC joints. Some patients may manifest premature pubarche and CC hyperandrogenism associated with skeletal dysplasia and short CC stature. {ECO:0000269|PubMed:19474428, CC ECO:0000269|PubMed:23633440, ECO:0000269|PubMed:23824674, CC ECO:0000269|PubMed:25594860, ECO:0000269|PubMed:9714015}. Note=The CC disease is caused by mutations affecting the gene represented in CC this entry. CC -!- SIMILARITY: In the N-terminal section; belongs to the APS kinase CC family. {ECO:0000305}. CC -!- SIMILARITY: In the C-terminal section; belongs to the sulfate CC adenylyltransferase 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; AF091242; AAC64583.1; -; mRNA. DR EMBL; AF074331; AAD38423.1; -; mRNA. DR EMBL; AF313907; AAK00296.1; -; mRNA. DR EMBL; AF160509; AAF40307.2; -; Genomic_DNA. DR EMBL; AF160503; AAF40307.2; JOINED; Genomic_DNA. DR EMBL; AF160504; AAF40307.2; JOINED; Genomic_DNA. DR EMBL; AF160505; AAF40307.2; JOINED; Genomic_DNA. DR EMBL; AF160506; AAF40307.2; JOINED; Genomic_DNA. DR EMBL; AF160507; AAF40307.2; JOINED; Genomic_DNA. DR EMBL; AF160508; AAF40307.2; JOINED; Genomic_DNA. DR EMBL; AF173365; AAF12761.1; -; mRNA. DR EMBL; AF150754; AAF20366.2; -; mRNA. DR EMBL; BC009894; AAH09894.1; -; mRNA. DR CCDS; CCDS44453.1; -. [O95340-2] DR CCDS; CCDS7385.1; -. [O95340-1] DR RefSeq; NP_001015880.1; NM_001015880.1. [O95340-2] DR RefSeq; NP_004661.2; NM_004670.3. [O95340-1] DR UniGene; Hs.524491; -. DR PDB; 2AX4; X-ray; 2.50 A; A/B/C/D=21-218. DR PDBsum; 2AX4; -. DR ProteinModelPortal; O95340; -. DR SMR; O95340; 21-613. DR BioGrid; 114521; 13. DR MINT; MINT-5000453; -. DR STRING; 9606.ENSP00000406157; -. DR PhosphoSite; O95340; -. DR BioMuta; PAPSS2; -. DR MaxQB; O95340; -. DR PaxDb; O95340; -. DR PRIDE; O95340; -. DR DNASU; 9060; -. DR Ensembl; ENST00000361175; ENSP00000354436; ENSG00000198682. [O95340-1] DR Ensembl; ENST00000456849; ENSP00000406157; ENSG00000198682. [O95340-2] DR GeneID; 9060; -. DR KEGG; hsa:9060; -. DR UCSC; uc001kew.3; human. [O95340-2] DR UCSC; uc001kex.3; human. [O95340-1] DR CTD; 9060; -. DR GeneCards; GC10P089409; -. DR HGNC; HGNC:8604; PAPSS2. DR MIM; 603005; gene. DR MIM; 612847; phenotype. DR neXtProt; NX_O95340; -. DR Orphanet; 93303; Brachyolmia type 1, Toledo type. DR Orphanet; 93282; Spondyloepimetaphyseal dysplasia, Pakistani type. DR PharmGKB; PA383; -. DR eggNOG; COG0529; -. DR GeneTree; ENSGT00390000009613; -. DR HOVERGEN; HBG053503; -. DR KO; K13811; -. DR OMA; QHPYIKM; -. DR OrthoDB; EOG74TWZ4; -. DR PhylomeDB; O95340; -. DR TreeFam; TF313143; -. DR BioCyc; MetaCyc:HS07544-MONOMER; -. DR BRENDA; 2.7.1.25; 2681. DR Reactome; REACT_268843; Defective PAPSS2 causes SEMD-PA. DR Reactome; REACT_6840; Transport and synthesis of PAPS. DR SABIO-RK; O95340; -. DR UniPathway; UPA00097; -. DR ChiTaRS; PAPSS2; human. DR EvolutionaryTrace; O95340; -. DR GeneWiki; PAPSS2; -. DR GenomeRNAi; 9060; -. DR NextBio; 33949; -. DR PRO; PR:O95340; -. DR Proteomes; UP000005640; Chromosome 10. DR Bgee; O95340; -. DR CleanEx; HS_PAPSS2; -. DR ExpressionAtlas; O95340; baseline and differential. DR Genevestigator; O95340; -. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0004020; F:adenylylsulfate kinase activity; IBA:GO_Central. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0016779; F:nucleotidyltransferase activity; ISS:UniProtKB. DR GO; GO:0004781; F:sulfate adenylyltransferase (ATP) activity; ISS:UniProtKB. DR GO; GO:0050428; P:3'-phosphoadenosine 5'-phosphosulfate biosynthetic process; TAS:Reactome. DR GO; GO:0050427; P:3'-phosphoadenosine 5'-phosphosulfate metabolic process; TAS:Reactome. DR GO; GO:0007596; P:blood coagulation; IEA:Ensembl. DR GO; GO:0060348; P:bone development; IEA:Ensembl. DR GO; GO:0005975; P:carbohydrate metabolic process; TAS:Reactome. DR GO; GO:0030203; P:glycosaminoglycan metabolic process; TAS:Reactome. DR GO; GO:0001501; P:skeletal system development; TAS:ProtInc. DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome. DR GO; GO:0000103; P:sulfate assimilation; IBA:GO_Central. DR GO; GO:0006805; P:xenobiotic metabolic process; TAS:Reactome. DR Gene3D; 3.40.50.300; -; 1. DR Gene3D; 3.40.50.620; -; 1. DR HAMAP; MF_00065; Adenylyl_sulf_kinase; 1. DR InterPro; IPR002891; APS_kinase. DR InterPro; IPR025980; ATP-Sase_PUA-like_dom. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR015947; PUA-like_domain. DR InterPro; IPR014729; Rossmann-like_a/b/a_fold. DR InterPro; IPR024951; Sulfurylase_cat_dom. DR InterPro; IPR002650; Sulphate_adenylyltransferase. DR Pfam; PF01583; APS_kinase; 1. DR Pfam; PF01747; ATP-sulfurylase; 1. DR Pfam; PF14306; PUA_2; 1. DR SUPFAM; SSF52540; SSF52540; 1. DR SUPFAM; SSF88697; SSF88697; 1. DR TIGRFAMs; TIGR00455; apsK; 1. DR TIGRFAMs; TIGR00339; sopT; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; ATP-binding; KW Complete proteome; Disease mutation; Dwarfism; Kinase; KW Multifunctional enzyme; Nucleotide-binding; Nucleotidyltransferase; KW Polymorphism; Reference proteome; Transferase. FT CHAIN 1 614 Bifunctional 3'-phosphoadenosine 5'- FT phosphosulfate synthase 2. FT /FTId=PRO_0000105961. FT NP_BIND 49 56 ATP. {ECO:0000255}. FT REGION 1 ?210 Adenylyl-sulfate kinase. FT REGION ?211 614 Sulfate adenylyltransferase. FT MOTIF 511 515 PP-motif. FT ACT_SITE 123 123 Phosphoserine intermediate. FT {ECO:0000250}. FT MOD_RES 5 5 N6-acetyllysine. FT {ECO:0000250|UniProtKB:Q60967}. FT VAR_SEQ 288 288 D -> DGMALP (in isoform B). FT {ECO:0000303|PubMed:10559207, FT ECO:0000303|Ref.6}. FT /FTId=VSP_001259. FT VARIANT 10 10 E -> K (significant decrease of activity; FT dbSNP:rs17173698). FT {ECO:0000269|PubMed:11773860}. FT /FTId=VAR_029136. FT VARIANT 43 43 C -> Y (in SEMD-PA; reduces strongly PAPS FT synthase activity). FT {ECO:0000269|PubMed:23824674}. FT /FTId=VAR_073026. FT VARIANT 48 48 T -> R (in SEMD-PA; patient with FT premature pubarche and hyperandrogenism; FT results in partial loss of activity; FT increases ubiquitin-dependent protein FT instability). FT {ECO:0000269|PubMed:19474428, FT ECO:0000269|PubMed:25594860}. FT /FTId=VAR_063049. FT VARIANT 76 76 L -> Q (in SEMD-PA; reduces strongly PAPS FT synthase activity). FT {ECO:0000269|PubMed:23824674}. FT /FTId=VAR_073027. FT VARIANT 183 183 E -> K (polymorphism; similar PAPS FT synthase activity as the wild-type). FT {ECO:0000269|PubMed:23824674}. FT /FTId=VAR_073028. FT VARIANT 270 270 G -> D (in SEMD-PA; increases ubiquitin- FT dependent protein instability). FT {ECO:0000269|PubMed:25594860}. FT /FTId=VAR_073029. FT VARIANT 281 281 M -> L (in dbSNP:rs45624631). FT {ECO:0000269|PubMed:11773860}. FT /FTId=VAR_029137. FT VARIANT 291 291 V -> M (significant decrease of activity; FT dbSNP:rs45467596). FT {ECO:0000269|PubMed:11773860}. FT /FTId=VAR_022077. FT VARIANT 432 432 R -> K. {ECO:0000269|PubMed:11773860}. FT /FTId=VAR_029138. FT CONFLICT 166 166 R -> K (in Ref. 2; AAD38423). FT {ECO:0000305}. FT CONFLICT 361 361 E -> G (in Ref. 3; AAK00296). FT {ECO:0000305}. FT CONFLICT 426 426 R -> C (in Ref. 1; AAC64583). FT {ECO:0000305}. FT CONFLICT 567 567 P -> L (in Ref. 2; AAD38423). FT {ECO:0000305}. FT HELIX 27 33 {ECO:0000244|PDB:2AX4}. FT STRAND 34 37 {ECO:0000244|PDB:2AX4}. FT STRAND 43 48 {ECO:0000244|PDB:2AX4}. FT HELIX 55 68 {ECO:0000244|PDB:2AX4}. FT STRAND 73 76 {ECO:0000244|PDB:2AX4}. FT HELIX 78 81 {ECO:0000244|PDB:2AX4}. FT TURN 82 88 {ECO:0000244|PDB:2AX4}. FT HELIX 93 112 {ECO:0000244|PDB:2AX4}. FT STRAND 116 120 {ECO:0000244|PDB:2AX4}. FT HELIX 126 138 {ECO:0000244|PDB:2AX4}. FT STRAND 143 149 {ECO:0000244|PDB:2AX4}. FT HELIX 152 158 {ECO:0000244|PDB:2AX4}. FT STRAND 160 162 {ECO:0000244|PDB:2AX4}. FT HELIX 163 168 {ECO:0000244|PDB:2AX4}. FT TURN 176 178 {ECO:0000244|PDB:2AX4}. FT STRAND 189 193 {ECO:0000244|PDB:2AX4}. FT HELIX 199 212 {ECO:0000244|PDB:2AX4}. SQ SEQUENCE 614 AA; 69501 MW; 52F4B6D972DDA91E CRC64; MSGIKKQKTE NQQKSTNVVY QAHHVSRNKR GQVVGTRGGF RGCTVWLTGL SGAGKTTISF ALEEYLVSHA IPCYSLDGDN VRHGLNRNLG FSPGDREENI RRIAEVAKLF ADAGLVCITS FISPFAKDRE NARKIHESAG LPFFEIFVDA PLNICESRDV KGLYKRARAG EIKGFTGIDS DYEKPETPER VLKTNLSTVS DCVHQVVELL QEQNIVPYTI IKDIHELFVP ENKLDHVRAE AETLPSLSIT KLDLQWVQVL SEGWATPLKG FMREKEYLQV MHFDTLLDDG VINMSIPIVL PVSAEDKTRL EGCSKFVLAH GGRRVAILRD AEFYEHRKEE RCSRVWGTTC TKHPHIKMVM ESGDWLVGGD LQVLEKIRWN DGLDQYRLTP LELKQKCKEM NADAVFAFQL RNPVHNGHAL LMQDTRRRLL ERGYKHPVLL LHPLGGWTKD DDVPLDWRMK QHAAVLEEGV LDPKSTIVAI FPSPMLYAGP TEVQWHCRSR MIAGANFYIV GRDPAGMPHP ETKKDLYEPT HGGKVLSMAP GLTSVEIIPF RVAAYNKAKK AMDFYDPARH NEFDFISGTR MRKLAREGEN PPDGFMAPKA WKVLTDYYRS LEKN //