NSMA3_MOUSE
ID NSMA3_MOUSE Reviewed; 823 AA.
AC Q6ZPR5; Q3TPE0; Q3TPP1; Q8CBJ5; Q8CD12; Q8CD83; Q8R0J3; Q9CX74;
DT 23-JAN-2007, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 2.
DT 03-AUG-2022, entry version 120.
DE RecName: Full=Sphingomyelin phosphodiesterase 4;
DE EC=3.1.4.12;
DE AltName: Full=Neutral sphingomyelinase 3;
DE Short=nSMase-3;
DE Short=nSMase3 {ECO:0000303|PubMed:25180167};
DE AltName: Full=Neutral sphingomyelinase III;
GN Name=Smpd4; Synonyms=Kiaa1418;
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 [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Embryonic tail;
RX PubMed=14621295; DOI=10.1093/dnares/10.4.167;
RA Okazaki N., Kikuno R., Ohara R., Inamoto S., Koseki H., Hiraoka S.,
RA Saga Y., Nagase T., Ohara O., Koga H.;
RT "Prediction of the coding sequences of mouse homologues of KIAA gene: III.
RT The complete nucleotide sequences of 500 mouse KIAA-homologous cDNAs
RT identified by screening of terminal sequences of cDNA clones randomly
RT sampled from size-fractionated libraries.";
RL DNA Res. 10:167-180(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2; 3; 4 AND 5).
RC STRAIN=C57BL/6J; TISSUE=Cerebellum, Head, Testis, and Thymus;
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] (ISOFORM 2).
RC STRAIN=FVB/N; TISSUE=Liver;
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 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-245, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brown adipose tissue, Kidney, Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [5]
RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, ALTERNATIVE SPLICING,
RP CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND COFACTOR.
RX PubMed=25180167; DOI=10.1016/j.redox.2014.07.006;
RA Moylan J.S., Smith J.D., Wolf Horrell E.M., McLean J.B., Deevska G.M.,
RA Bonnell M.R., Nikolova-Karakashian M.N., Reid M.B.;
RT "Neutral sphingomyelinase-3 mediates TNF-stimulated oxidant activity in
RT skeletal muscle.";
RL Redox Biol. 2:910-920(2014).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY, AND SUBCELLULAR LOCATION.
RX PubMed=31142202; DOI=10.1080/19491034.2019.1618175;
RA Cheng L.C., Baboo S., Lindsay C., Brusman L., Martinez-Bartolome S.,
RA Tapia O., Zhang X., Yates J.R. III, Gerace L.;
RT "Identification of new transmembrane proteins concentrated at the nuclear
RT envelope using organellar proteomics of mesenchymal cells.";
RL Nucleus 10:126-143(2019).
CC -!- FUNCTION: Catalyzes the hydrolysis of membrane sphingomyelin to form
CC phosphorylcholine and ceramide (PubMed:25180167). It has a relevant
CC role in the homeostasis of membrane sphingolipids, thereby influencing
CC membrane integrity, and endoplasmic reticulum organization and
CC function. May sensitize cells to DNA damage-induced apoptosis. In
CC skeletal muscle, mediates TNF-stimulated oxidant production
CC (PubMed:25180167). {ECO:0000250|UniProtKB:Q9NXE4,
CC ECO:0000269|PubMed:25180167}.
CC -!- CATALYTIC ACTIVITY: [Isoform 1]:
CC Reaction=a sphingomyelin + H2O = 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 Evidence={ECO:0000269|PubMed:25180167};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19254;
CC Evidence={ECO:0000305|PubMed:25180167};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:25180167};
CC -!- ACTIVITY REGULATION: Activated by phosphatidylserine and tumor necrosis
CC factor (TNF) (PubMed:25180167). Inhibited by scyphostatin (By
CC similarity). {ECO:0000250|UniProtKB:Q9NXE4,
CC ECO:0000269|PubMed:25180167}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:25180167}; Single-pass membrane protein
CC {ECO:0000255}. Golgi apparatus membrane {ECO:0000250|UniProtKB:Q9NXE4};
CC Single-pass membrane protein {ECO:0000255}. Nucleus envelope
CC {ECO:0000269|PubMed:31142202}. Cell membrane, sarcolemma
CC {ECO:0000269|PubMed:25180167}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1; Synonyms=nSMase3a {ECO:0000303|PubMed:25180167};
CC IsoId=Q6ZPR5-1; Sequence=Displayed;
CC Name=2; Synonyms=nSMase3b {ECO:0000303|PubMed:25180167};
CC IsoId=Q6ZPR5-2; Sequence=VSP_022485;
CC Name=3;
CC IsoId=Q6ZPR5-3; Sequence=VSP_022485, VSP_022486;
CC Name=4;
CC IsoId=Q6ZPR5-4; Sequence=VSP_022485, VSP_022487;
CC Name=5;
CC IsoId=Q6ZPR5-5; Sequence=VSP_022484, VSP_022485;
CC -!- TISSUE SPECIFICITY: [Isoform 1]: Expressed in skeletal muscle (at
CC protein level). {ECO:0000269|PubMed:25180167}.
CC -!- TISSUE SPECIFICITY: [Isoform 2]: Expressed in skeletal muscle but a
CC lower levels than isoform 1 (at protein level).
CC {ECO:0000269|PubMed:25180167}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAC98164.1; Type=Erroneous initiation; Note=Extended 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; AK129354; BAC98164.1; ALT_INIT; mRNA.
DR EMBL; AK019466; BAB31737.1; -; mRNA.
DR EMBL; AK031029; BAC27221.1; -; mRNA.
DR EMBL; AK031685; BAC27512.1; -; mRNA.
DR EMBL; AK035892; BAC29229.1; -; mRNA.
DR EMBL; AK164234; BAE37694.1; -; mRNA.
DR EMBL; AK164456; BAE37796.1; -; mRNA.
DR EMBL; BC026767; AAH26767.1; -; mRNA.
DR CCDS; CCDS28009.1; -. [Q6ZPR5-1]
DR CCDS; CCDS49779.1; -. [Q6ZPR5-3]
DR CCDS; CCDS49780.1; -. [Q6ZPR5-4]
DR CCDS; CCDS49781.1; -. [Q6ZPR5-2]
DR RefSeq; NP_001158081.1; NM_001164609.1. [Q6ZPR5-4]
DR RefSeq; NP_001158082.1; NM_001164610.1. [Q6ZPR5-2]
DR RefSeq; NP_001158083.1; NM_001164611.1. [Q6ZPR5-3]
DR RefSeq; NP_084221.2; NM_029945.3. [Q6ZPR5-1]
DR RefSeq; XP_006522785.1; XM_006522722.2. [Q6ZPR5-1]
DR AlphaFoldDB; Q6ZPR5; -.
DR BioGRID; 218808; 2.
DR IntAct; Q6ZPR5; 2.
DR STRING; 10090.ENSMUSP00000006053; -.
DR SwissLipids; SLP:000001481; -. [Q6ZPR5-1]
DR iPTMnet; Q6ZPR5; -.
DR PhosphoSitePlus; Q6ZPR5; -.
DR EPD; Q6ZPR5; -.
DR MaxQB; Q6ZPR5; -.
DR PaxDb; Q6ZPR5; -.
DR PeptideAtlas; Q6ZPR5; -.
DR PRIDE; Q6ZPR5; -.
DR ProteomicsDB; 253024; -. [Q6ZPR5-1]
DR ProteomicsDB; 253025; -. [Q6ZPR5-2]
DR ProteomicsDB; 253026; -. [Q6ZPR5-3]
DR ProteomicsDB; 253027; -. [Q6ZPR5-4]
DR ProteomicsDB; 253028; -. [Q6ZPR5-5]
DR Antibodypedia; 56085; 89 antibodies from 20 providers.
DR DNASU; 77626; -.
DR Ensembl; ENSMUST00000006053; ENSMUSP00000006053; ENSMUSG00000005899. [Q6ZPR5-1]
DR Ensembl; ENSMUST00000090159; ENSMUSP00000087620; ENSMUSG00000005899. [Q6ZPR5-4]
DR Ensembl; ENSMUST00000163476; ENSMUSP00000131867; ENSMUSG00000005899. [Q6ZPR5-2]
DR Ensembl; ENSMUST00000165363; ENSMUSP00000130720; ENSMUSG00000005899. [Q6ZPR5-3]
DR GeneID; 77626; -.
DR KEGG; mmu:77626; -.
DR UCSC; uc007yll.2; mouse. [Q6ZPR5-1]
DR UCSC; uc007ylm.2; mouse. [Q6ZPR5-3]
DR UCSC; uc007yln.2; mouse. [Q6ZPR5-4]
DR UCSC; uc007ylo.2; mouse. [Q6ZPR5-2]
DR UCSC; uc007ylp.2; mouse. [Q6ZPR5-5]
DR CTD; 55627; -.
DR MGI; MGI:1924876; Smpd4.
DR VEuPathDB; HostDB:ENSMUSG00000005899; -.
DR eggNOG; KOG4396; Eukaryota.
DR GeneTree; ENSGT00390000006044; -.
DR HOGENOM; CLU_012098_0_0_1; -.
DR InParanoid; Q6ZPR5; -.
DR OMA; AYAWRSE; -.
DR OrthoDB; 470341at2759; -.
DR PhylomeDB; Q6ZPR5; -.
DR TreeFam; TF324409; -.
DR Reactome; R-MMU-1660662; Glycosphingolipid metabolism.
DR BioGRID-ORCS; 77626; 4 hits in 74 CRISPR screens.
DR ChiTaRS; Smpd4; mouse.
DR PRO; PR:Q6ZPR5; -.
DR Proteomes; UP000000589; Chromosome 16.
DR RNAct; Q6ZPR5; protein.
DR Bgee; ENSMUSG00000005899; Expressed in embryonic post-anal tail and 256 other tissues.
DR ExpressionAtlas; Q6ZPR5; baseline and differential.
DR Genevisible; Q6ZPR5; MM.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005794; C:Golgi apparatus; ISS:HGNC-UCL.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005635; C:nuclear envelope; IDA:UniProtKB.
DR GO; GO:0005640; C:nuclear outer membrane; ISO:MGI.
DR GO; GO:0042383; C:sarcolemma; IDA:UniProtKB.
DR GO; GO:0005802; C:trans-Golgi network; ISS:HGNC-UCL.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004767; F:sphingomyelin phosphodiesterase activity; IDA:UniProtKB.
DR GO; GO:0050290; F:sphingomyelin phosphodiesterase D activity; ISS:HGNC-UCL.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IDA:UniProtKB.
DR GO; GO:0046513; P:ceramide biosynthetic process; IDA:UniProtKB.
DR GO; GO:0007029; P:endoplasmic reticulum organization; ISO:MGI.
DR GO; GO:0046475; P:glycerophospholipid catabolic process; ISO:MGI.
DR GO; GO:0001701; P:in utero embryonic development; IMP:MGI.
DR GO; GO:0006685; P:sphingomyelin catabolic process; IDA:UniProtKB.
DR InterPro; IPR024129; Sphingomy_SMPD4.
DR PANTHER; PTHR12988; PTHR12988; 1.
DR Pfam; PF14724; mit_SMPDase; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell membrane; Endoplasmic reticulum;
KW Golgi apparatus; Hydrolase; Lipid metabolism; Magnesium; Membrane;
KW Metal-binding; Nucleus; Phosphoprotein; Reference proteome; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..823
FT /note="Sphingomyelin phosphodiesterase 4"
FT /id="PRO_0000273164"
FT TRANSMEM 776..796
FT /note="Helical"
FT /evidence="ECO:0000255"
FT MOD_RES 130
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9NXE4"
FT MOD_RES 245
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 665
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9NXE4"
FT MOD_RES 749
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9NXE4"
FT VAR_SEQ 1..157
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_022484"
FT VAR_SEQ 288..316
FT /note="Missing (in isoform 2, isoform 3, isoform 4 and
FT isoform 5)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:16141072"
FT /id="VSP_022485"
FT VAR_SEQ 429
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_022486"
FT VAR_SEQ 429
FT /note="W -> CLAPWSPYQHRGLR (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_022487"
FT CONFLICT 7
FT /note="Q -> P (in Ref. 3; AAH26767)"
FT /evidence="ECO:0000305"
FT CONFLICT 15
FT /note="S -> T (in Ref. 2; BAC27221)"
FT /evidence="ECO:0000305"
FT CONFLICT 141
FT /note="P -> T (in Ref. 2; BAC27512)"
FT /evidence="ECO:0000305"
FT CONFLICT 195
FT /note="F -> V (in Ref. 3; AAH26767)"
FT /evidence="ECO:0000305"
FT CONFLICT 368
FT /note="V -> E (in Ref. 2; BAB31737)"
FT /evidence="ECO:0000305"
FT CONFLICT 732
FT /note="F -> Y (in Ref. 2; BAC27221)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 823 AA; 93276 MW; 3C082D335608BA70 CRC64;
MAFPHLQQPS FLLASLKADS INKPFAQRCQ DLVKVIEDFP AKELHAVFPW LVESIFGSLD
GVLVGWNLRC LQGRVNPVEY STAMEFLDPS GPMMKLVYKL QAEDYNFDFP VSCLPGPVKA
SIQENVLPDS PLYHNKVQFP PTGGLGLNLA LNPFEYYMFY FALSLISQKP MSMTLHVRTS
DCAYFTLVDR YLSWFLPTEG SVPPPLCSSP GGSSPSPAPR TPAMPFASYG LHTSLLKRHI
SHQTSVNADP ASHEIWRSET LLQVFVEMWL HHYSLEMYQK MQSPHAKLEV LHYRLTVSSA
LHSPAQPSLQ ALHAYQESFT PTEEHVLVVR LLLKHLHAFA NSLKPDQASP SAHSHATSPL
EEFKRAAVPR FVQQKLYVFL QHCFGHWPLD ATFRAVLEMW LSYLQPWRYA PEKQAQGSDP
QPRCVSEKWA PFIQENLLMY TKLFVSFLNR ALRTDLVSPK NALMVFRVAK VFAQPNLAEM
IQKGEQLFLE PELIIPHRQH RLFTVTTSFL SPWPPVVTDA SFKVKSHVYS LEGQDCKYTP
MFGPEIRTLV LRLAQLITQA KQTAKSISDQ YVESPTGRSF LSWLTFGLTD TNSCYPANDL
DEIGQDSIRK TDEYLEKALE YLRQIFRLSE AQLAQLTLAL GSARDENGKQ QLPDCIVGEE
GLILTPLGRY QIINGLRRFE IEYQGDLELQ PIRSYEITSL VRALFRLSSA INRRFAGQMA
ALCSRNDFLG SFCRYHLTEP ALSNRHLLSP VGRRQVTNPA RGPRLSLRFL GSYRTLLLLL
MAFFVASLFC IGPLSCSLLL VLGYVLYAIA MTLLTERGKL HQL