ID NSMA2_HUMAN Reviewed; 655 AA. AC Q9NY59; B7ZL82; Q2M1S8; DT 30-AUG-2005, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-2000, sequence version 1. DT 12-AUG-2020, entry version 146. DE RecName: Full=Sphingomyelin phosphodiesterase 3; DE EC=3.1.4.12; DE AltName: Full=Neutral sphingomyelinase 2; DE Short=nSMase-2; DE Short=nSMase2; DE AltName: Full=Neutral sphingomyelinase II; GN Name=SMPD3; 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 [MRNA] (ISOFORM 1), FUNCTION, COFACTOR, ACTIVITY RP REGULATION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=10823942; DOI=10.1073/pnas.97.11.5895; RA Hofmann K., Tomiuk S., Wolff G., Stoffel W.; RT "Cloning and characterization of the mammalian brain-specific, Mg2+- RT dependent neutral sphingomyelinase."; RL Proc. Natl. Acad. Sci. U.S.A. 97:5895-5900(2000). 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 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). 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. RX PubMed=14741383; DOI=10.1016/s0014-5793(03)01523-0; RA Miura Y., Gotoh E., Nara F., Nishijima M., Hanada K.; RT "Hydrolysis of sphingosylphosphocholine by neutral sphingomyelinases."; RL FEBS Lett. 557:288-292(2004). RN [5] RP FUNCTION, COFACTOR, AND SUBCELLULAR LOCATION. RX PubMed=15051724; DOI=10.1074/jbc.m313662200; RA Marchesini N., Osta W., Bielawski J., Luberto C., Obeid L.M., Hannun Y.A.; RT "Role for mammalian neutral sphingomyelinase 2 in confluence-induced growth RT arrest of MCF7 cells."; RL J. Biol. Chem. 279:25101-25111(2004). RN [6] RP TOPOLOGY. RX PubMed=17349629; DOI=10.1016/j.febslet.2007.02.046; RA Tani M., Hannun Y.A.; RT "Analysis of membrane topology of neutral sphingomyelinase 2."; RL FEBS Lett. 581:1323-1328(2007). RN [7] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-291, AND IDENTIFICATION BY RP 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., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). CC -!- FUNCTION: Catalyzes the hydrolysis of sphingomyelin to form ceramide CC and phosphocholine. Ceramide mediates numerous cellular functions, such CC as apoptosis and growth arrest, and is capable of regulating these 2 CC cellular events independently. Also hydrolyzes CC sphingosylphosphocholine. Regulates the cell cycle by acting as a CC growth suppressor in confluent cells. Probably acts as a regulator of CC postnatal development and participates in bone and dentin CC mineralization. {ECO:0000269|PubMed:10823942, CC ECO:0000269|PubMed:14741383, ECO:0000269|PubMed:15051724}. CC -!- CATALYTIC ACTIVITY: CC Reaction=H2O + sphingomyelin = an N-acylsphing-4-enine + H(+) + CC phosphocholine; Xref=Rhea:RHEA:19253, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:17636, ChEBI:CHEBI:52639, CC ChEBI:CHEBI:295975; EC=3.1.4.12; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:10823942, ECO:0000269|PubMed:15051724}; CC -!- ACTIVITY REGULATION: Activated by unsaturated fatty acids and CC phosphatidylserine. {ECO:0000269|PubMed:10823942}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC pH dependence: CC Optimum pH is 7.5.; CC -!- PATHWAY: Lipid metabolism; sphingolipid metabolism. CC -!- INTERACTION: CC Q9NY59; O75530: EED; NbExp=2; IntAct=EBI-715400, EBI-923794; CC -!- SUBCELLULAR LOCATION: Golgi apparatus membrane CC {ECO:0000269|PubMed:10823942}; Lipid-anchor CC {ECO:0000269|PubMed:10823942}. Cell membrane CC {ECO:0000269|PubMed:15051724}; Lipid-anchor CC {ECO:0000269|PubMed:15051724}. Note=May localize to detergent-resistant CC subdomains of Golgi membranes of hypothalamic neurosecretory neurons CC (PubMed:10823942). Localizes to plasma membrane in confluent contact- CC inhaibited cells (PubMed:15051724). CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q9NY59-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9NY59-2; Sequence=VSP_054334; CC -!- TISSUE SPECIFICITY: Predominantly expressed in brain. CC {ECO:0000269|PubMed:10823942}. CC -!- DEVELOPMENTAL STAGE: Up-regulated during G0/G1 phases. CC -!- PTM: Palmitoylated, palmitoylation-deficient proteins are targeted for CC lysosomal degradation. {ECO:0000250}. CC -!- SIMILARITY: Belongs to the neutral sphingomyelinase family. CC {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; AJ250460; CAB92964.1; -; mRNA. DR EMBL; AC099521; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC112238; AAI12239.1; -; mRNA. DR EMBL; BC143631; AAI43632.1; -; mRNA. DR CCDS; CCDS10867.1; -. [Q9NY59-1] DR RefSeq; NP_061137.1; NM_018667.3. [Q9NY59-1] DR RefSeq; XP_005256088.1; XM_005256031.3. [Q9NY59-1] DR RefSeq; XP_005256089.1; XM_005256032.3. [Q9NY59-1] DR RefSeq; XP_011521509.1; XM_011523207.1. [Q9NY59-1] DR RefSeq; XP_011521510.1; XM_011523208.2. [Q9NY59-1] DR RefSeq; XP_011521511.1; XM_011523209.2. [Q9NY59-1] DR RefSeq; XP_016878894.1; XM_017023405.1. [Q9NY59-1] DR RefSeq; XP_016878895.1; XM_017023406.1. [Q9NY59-1] DR RefSeq; XP_016878896.1; XM_017023407.1. [Q9NY59-1] DR RefSeq; XP_016878897.1; XM_017023408.1. [Q9NY59-1] DR PDB; 5UVG; X-ray; 1.85 A; A=117-651. DR PDBsum; 5UVG; -. DR SMR; Q9NY59; -. DR BioGRID; 120692; 13. DR DIP; DIP-60431N; -. DR IntAct; Q9NY59; 22. DR STRING; 9606.ENSP00000219334; -. DR DrugBank; DB00144; Phosphatidyl serine. DR SwissLipids; SLP:000001111; -. DR iPTMnet; Q9NY59; -. DR PhosphoSitePlus; Q9NY59; -. DR SwissPalm; Q9NY59; -. DR BioMuta; SMPD3; -. DR DMDM; 73921262; -. DR jPOST; Q9NY59; -. DR MassIVE; Q9NY59; -. DR PaxDb; Q9NY59; -. DR PeptideAtlas; Q9NY59; -. DR PRIDE; Q9NY59; -. DR ProteomicsDB; 7214; -. DR ProteomicsDB; 83180; -. [Q9NY59-1] DR Antibodypedia; 29783; 163 antibodies. DR DNASU; 55512; -. DR Ensembl; ENST00000219334; ENSP00000219334; ENSG00000103056. [Q9NY59-1] DR Ensembl; ENST00000563226; ENSP00000455955; ENSG00000103056. [Q9NY59-2] DR GeneID; 55512; -. DR KEGG; hsa:55512; -. DR UCSC; uc002ewa.4; human. [Q9NY59-1] DR CTD; 55512; -. DR DisGeNET; 55512; -. DR EuPathDB; HostDB:ENSG00000103056.11; -. DR GeneCards; SMPD3; -. DR HGNC; HGNC:14240; SMPD3. DR HPA; ENSG00000103056; Tissue enhanced (blood, intestine, lymphoid tissue). DR MIM; 605777; gene. DR neXtProt; NX_Q9NY59; -. DR OpenTargets; ENSG00000103056; -. DR PharmGKB; PA37862; -. DR eggNOG; ENOG502QVS2; Eukaryota. DR GeneTree; ENSGT00400000022168; -. DR HOGENOM; CLU_028243_0_0_1; -. DR InParanoid; Q9NY59; -. DR KO; K12352; -. DR OMA; HAVSWAL; -. DR OrthoDB; 455705at2759; -. DR PhylomeDB; Q9NY59; -. DR TreeFam; TF328678; -. DR BRENDA; 3.1.4.12; 2681. DR PathwayCommons; Q9NY59; -. DR Reactome; R-HSA-1660662; Glycosphingolipid metabolism. DR Reactome; R-HSA-5626978; TNFR1-mediated ceramide production. DR UniPathway; UPA00222; -. DR BioGRID-ORCS; 55512; 32 hits in 870 CRISPR screens. DR ChiTaRS; SMPD3; human. DR GeneWiki; SMPD3; -. DR GenomeRNAi; 55512; -. DR Pharos; Q9NY59; Tbio. DR PRO; PR:Q9NY59; -. DR Proteomes; UP000005640; Chromosome 16. DR RNAct; Q9NY59; protein. DR Bgee; ENSG00000103056; Expressed in small intestine and 166 other tissues. DR ExpressionAtlas; Q9NY59; baseline and differential. DR Genevisible; Q9NY59; HS. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0000137; C:Golgi cis cisterna; IEA:Ensembl. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0042802; F:identical protein binding; IEA:Ensembl. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0061751; F:neutral sphingomyelin phosphodiesterase activity; IEA:Ensembl. DR GO; GO:0004620; F:phospholipase activity; IBA:GO_Central. DR GO; GO:0004767; F:sphingomyelin phosphodiesterase activity; IBA:GO_Central. DR GO; GO:0030509; P:BMP signaling pathway; IEA:Ensembl. DR GO; GO:0098868; P:bone growth; IEA:Ensembl. DR GO; GO:0030282; P:bone mineralization; IEA:Ensembl. DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IEA:Ensembl. DR GO; GO:0071286; P:cellular response to magnesium ion; IEA:Ensembl. DR GO; GO:0140052; P:cellular response to oxidised low-density lipoprotein particle stimulus; IEA:Ensembl. DR GO; GO:1901653; P:cellular response to peptide; IEA:Ensembl. DR GO; GO:0071461; P:cellular response to redox state; IEA:Ensembl. DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IEA:Ensembl. DR GO; GO:0006672; P:ceramide metabolic process; IEA:Ensembl. DR GO; GO:0003433; P:chondrocyte development involved in endochondral bone morphogenesis; IEA:Ensembl. DR GO; GO:0032963; P:collagen metabolic process; IEA:Ensembl. DR GO; GO:0097187; P:dentinogenesis; IEA:Ensembl. DR GO; GO:0071897; P:DNA biosynthetic process; IEA:Ensembl. DR GO; GO:0001958; P:endochondral ossification; IEA:Ensembl. DR GO; GO:0085029; P:extracellular matrix assembly; IEA:Ensembl. DR GO; GO:0070314; P:G1 to G0 transition; IEA:Ensembl. DR GO; GO:0006687; P:glycosphingolipid metabolic process; TAS:Reactome. DR GO; GO:0002244; P:hematopoietic progenitor cell differentiation; IEA:Ensembl. DR GO; GO:0048286; P:lung alveolus development; IEA:Ensembl. DR GO; GO:0140014; P:mitotic nuclear division; IEA:Ensembl. DR GO; GO:0035264; P:multicellular organism growth; IEA:Ensembl. DR GO; GO:1900126; P:negative regulation of hyaluronan biosynthetic process; IEA:Ensembl. DR GO; GO:0030072; P:peptide hormone secretion; IEA:Ensembl. DR GO; GO:0048008; P:platelet-derived growth factor receptor signaling pathway; IEA:Ensembl. DR GO; GO:0015774; P:polysaccharide transport; IEA:Ensembl. DR GO; GO:2000304; P:positive regulation of ceramide biosynthetic process; TAS:Reactome. DR GO; GO:1903543; P:positive regulation of exosomal secretion; ISS:BHF-UCL. DR GO; GO:0045840; P:positive regulation of mitotic nuclear division; IEA:Ensembl. DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IEA:Ensembl. DR GO; GO:0043491; P:protein kinase B signaling; IEA:Ensembl. DR GO; GO:0061035; P:regulation of cartilage development; IEA:Ensembl. DR GO; GO:0002685; P:regulation of leukocyte migration; IEA:Ensembl. DR GO; GO:0001932; P:regulation of protein phosphorylation; IEA:Ensembl. DR GO; GO:0090520; P:sphingolipid mediated signaling pathway; IEA:Ensembl. DR GO; GO:0006685; P:sphingomyelin catabolic process; TAS:ProtInc. DR GO; GO:0006684; P:sphingomyelin metabolic process; IBA:GO_Central. DR InterPro; IPR036691; Endo/exonu/phosph_ase_sf. DR SUPFAM; SSF56219; SSF56219; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell cycle; Cell membrane; KW Developmental protein; Golgi apparatus; Hydrolase; Lipid metabolism; KW Lipoprotein; Magnesium; Membrane; Metal-binding; Palmitate; Phosphoprotein; KW Reference proteome; Sphingolipid metabolism. FT CHAIN 1..655 FT /note="Sphingomyelin phosphodiesterase 3" FT /id="PRO_0000075692" FT TOPO_DOM 1..10 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT INTRAMEM 11..31 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 32..64 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT INTRAMEM 65..85 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 86..655 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT ACT_SITE 639 FT /note="Proton acceptor" FT /evidence="ECO:0000250" FT METAL 364 FT /note="Magnesium" FT /evidence="ECO:0000250" FT SITE 512 FT /note="Important for substrate recognition" FT /evidence="ECO:0000250" FT MOD_RES 178 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9JJY3" FT MOD_RES 291 FT /note="Phosphoserine" FT /evidence="ECO:0000244|PubMed:24275569" FT LIPID 53 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000250" FT LIPID 54 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000250" FT LIPID 59 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000250" FT LIPID 397 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000250" FT LIPID 398 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000250" FT VAR_SEQ 541..548 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_054334" FT STRAND 122..133 FT /evidence="ECO:0000244|PDB:5UVG" FT HELIX 136..138 FT /evidence="ECO:0000244|PDB:5UVG" FT HELIX 147..163 FT /evidence="ECO:0000244|PDB:5UVG" FT STRAND 343..352 FT /evidence="ECO:0000244|PDB:5UVG" FT STRAND 359..365 FT /evidence="ECO:0000244|PDB:5UVG" FT HELIX 368..378 FT /evidence="ECO:0000244|PDB:5UVG" FT TURN 379..381 FT /evidence="ECO:0000244|PDB:5UVG" FT STRAND 383..386 FT /evidence="ECO:0000244|PDB:5UVG" FT HELIX 389..392 FT /evidence="ECO:0000244|PDB:5UVG" FT STRAND 408..413 FT /evidence="ECO:0000244|PDB:5UVG" FT STRAND 415..422 FT /evidence="ECO:0000244|PDB:5UVG" FT STRAND 436..446 FT /evidence="ECO:0000244|PDB:5UVG" FT STRAND 452..461 FT /evidence="ECO:0000244|PDB:5UVG" FT HELIX 469..489 FT /evidence="ECO:0000244|PDB:5UVG" FT STRAND 500..510 FT /evidence="ECO:0000244|PDB:5UVG" FT HELIX 518..520 FT /evidence="ECO:0000244|PDB:5UVG" FT HELIX 521..524 FT /evidence="ECO:0000244|PDB:5UVG" FT HELIX 528..531 FT /evidence="ECO:0000244|PDB:5UVG" FT STRAND 537..539 FT /evidence="ECO:0000244|PDB:5UVG" FT HELIX 565..572 FT /evidence="ECO:0000244|PDB:5UVG" FT HELIX 575..581 FT /evidence="ECO:0000244|PDB:5UVG" FT TURN 588..590 FT /evidence="ECO:0000244|PDB:5UVG" FT STRAND 591..593 FT /evidence="ECO:0000244|PDB:5UVG" FT HELIX 596..598 FT /evidence="ECO:0000244|PDB:5UVG" FT STRAND 607..616 FT /evidence="ECO:0000244|PDB:5UVG" FT STRAND 620..630 FT /evidence="ECO:0000244|PDB:5UVG" FT TURN 632..636 FT /evidence="ECO:0000244|PDB:5UVG" FT STRAND 642..650 FT /evidence="ECO:0000244|PDB:5UVG" SQ SEQUENCE 655 AA; 71081 MW; C06401571633C48E CRC64; MVLYTTPFPN SCLSALHCVS WALIFPCYWL VDRLAASFIP TTYEKRQRAD DPCCLQLLCT ALFTPIYLAL LVASLPFAFL GFLFWSPLQS ARRPYIYSRL EDKGLAGGAA LLSEWKGTGP GKSFCFATAN VCLLPDSLAR VNNLFNTQAR AKEIGQRIRN GAARPQIKIY IDSPTNTSIS AASFSSLVSP QGGDGVARAV PGSIKRTASV EYKGDGGRHP GDEAANGPAS GDPVDSSSPE DACIVRIGGE EGGRPPEADD PVPGGQARNG AGGGPRGQTP NHNQQDGDSG SLGSPSASRE SLVKGRAGPD TSASGEPGAN SKLLYKASVV KKAAARRRRH PDEAFDHEVS AFFPANLDFL CLQEVFDKRA ATKLKEQLHG YFEYILYDVG VYGCQGCCSF KCLNSGLLFA SRYPIMDVAY HCYPNKCNDD ALASKGALFL KVQVGSTPQD QRIVGYIACT HLHAPQEDSA IRCGQLDLLQ DWLADFRKST SSSSAANPEE LVAFDVVCGD FNFDNCSSDD KLEQQHSLFT HYRDPCRLGP GEEKPWAIGT LLDTNGLYDE DVCTPDNLQK VLESEEGRRE YLAFPTSKSS GQKGRKELLK GNGRRIDYML HAEEGLCPDW KAEVEEFSFI TQLSGLTDHL PVAMRLMVSS GEEEA //