NSMA3_HUMAN
ID NSMA3_HUMAN Reviewed; 866 AA.
AC Q9NXE4; B1PBA3; B4DM23; B4DQ31; B4DRB8; B4DWK7; B4E0L6; E7ESA2; E9PCE6;
AC Q6FI76; Q6P1P7; Q6ZT43; Q9H0M2; Q9NW20; Q9NWL2; Q9P2C9;
DT 23-JAN-2007, integrated into UniProtKB/Swiss-Prot.
DT 28-MAR-2018, sequence version 3.
DT 03-AUG-2022, entry version 146.
DE RecName: Full=Sphingomyelin phosphodiesterase 4 {ECO:0000305};
DE EC=3.1.4.12 {ECO:0000269|PubMed:16517606};
DE AltName: Full=Neutral sphingomyelinase 3 {ECO:0000303|PubMed:18505924};
DE Short=nSMase-3 {ECO:0000303|PubMed:18505924};
DE Short=nSMase3 {ECO:0000303|PubMed:18505924};
DE AltName: Full=Neutral sphingomyelinase III;
GN Name=SMPD4 {ECO:0000312|HGNC:HGNC:32949}; Synonyms=KIAA1418, SKNY;
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], FUNCTION, SUBCELLULAR LOCATION, INDUCTION BY
RP DNA-DAMAGE, MUTAGENESIS OF 862-LYS--GLN-865, AND TISSUE SPECIFICITY.
RX PubMed=18505924; DOI=10.1158/1541-7786.mcr-07-2097;
RA Corcoran C.A., He Q., Ponnusamy S., Ogretmen B., Huang Y., Sheikh M.S.;
RT "Neutral sphingomyelinase-3 is a DNA damage and nongenotoxic stress-
RT regulated gene that is deregulated in human malignancies.";
RL Mol. Cancer Res. 6:795-807(2008).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=10718198; DOI=10.1093/dnares/7.1.65;
RA Nagase T., Kikuno R., Ishikawa K., Hirosawa M., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XVI. The
RT complete sequences of 150 new cDNA clones from brain which code for large
RT proteins in vitro.";
RL DNA Res. 7:65-73(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2; 4; 5; 6; 7; 8 AND 9),
RP AND NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 173-866 (ISOFORM 4).
RC TISSUE=Mammary gland, and Thymus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Lung;
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 436-866.
RC TISSUE=Testis;
RX PubMed=11230166; DOI=10.1101/gr.gr1547r;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J.,
RA Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W.,
RA Ottenwaelder B., Obermaier B., Tampe J., Heubner D., Wambutt R., Korn B.,
RA Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and analysis of
RT 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 439-866.
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP FUNCTION, COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY REGULATION,
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=16517606; DOI=10.1074/jbc.m511306200;
RA Krut O., Wiegmann K., Kashkar H., Yazdanpanah B., Kroenke M.;
RT "Novel tumor necrosis factor-responsive mammalian neutral sphingomyelinase-
RT 3 is a C-tail-anchored protein.";
RL J. Biol. Chem. 281:13784-13793(2006).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-169 AND THR-708, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-169, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [12]
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., Buerckstuemmer T.,
RA 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 [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-169 AND SER-792, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [15]
RP FUNCTION, CATALYTIC ACTIVITY, AND TISSUE SPECIFICITY.
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 [16]
RP FUNCTION, SUBCELLULAR LOCATION, INVOLVEMENT IN NEDMABA, AND VARIANTS
RP NEDMABA 67-GLN--PRO-866 DEL; 124-GLU--PRO-866 DEL; PRO-231; LEU-446;
RP VAL-661 AND 761-GLN--PRO-866 DEL.
RX PubMed=31495489; DOI=10.1016/j.ajhg.2019.08.006;
RA Magini P., Smits D.J., Vandervore L., Schot R., Columbaro M.,
RA Kasteleijn E., van der Ent M., Palombo F., Lequin M.H., Dremmen M.,
RA de Wit M.C.Y., Severino M., Divizia M.T., Striano P., Ordonez-Herrera N.,
RA Alhashem A., Al Fares A., Al Ghamdi M., Rolfs A., Bauer P., Demmers J.,
RA Verheijen F.W., Wilke M., van Slegtenhorst M., van der Spek P.J., Seri M.,
RA Jansen A.C., Stottmann R.W., Hufnagel R.B., Hopkin R.J., Aljeaid D.,
RA Wiszniewski W., Gawlinski P., Laure-Kamionowska M., Alkuraya F.S.,
RA Akleh H., Stanley V., Musaev D., Gleeson J.G., Zaki M.S.,
RA Brunetti-Pierri N., Cappuccio G., Davidov B., Basel-Salmon L., Bazak L.,
RA Shahar N.R., Bertoli-Avella A., Mirzaa G.M., Dobyns W.B., Pippucci T.,
RA Fornerod M., Mancini G.M.S.;
RT "Loss of SMPD4 causes a developmental disorder characterized by
RT microcephaly and congenital arthrogryposis.";
RL Am. J. Hum. Genet. 105:689-705(2019).
CC -!- FUNCTION: Catalyzes the hydrolysis of membrane sphingomyelin to form
CC phosphorylcholine and ceramide (PubMed:16517606, PubMed:25180167). It
CC has a relevant role in the homeostasis of membrane sphingolipids,
CC thereby influencing membrane integrity, and endoplasmic reticulum
CC organization and function (PubMed:31495489). May sensitize cells to DNA
CC damage-induced apoptosis (PubMed:18505924). In skeletal muscle,
CC mediates TNF-stimulated oxidant production (By similarity).
CC {ECO:0000250|UniProtKB:Q6ZPR5, ECO:0000269|PubMed:16517606,
CC ECO:0000269|PubMed:18505924, ECO:0000269|PubMed:25180167,
CC ECO:0000269|PubMed:31495489}.
CC -!- CATALYTIC ACTIVITY:
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:16517606, 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:16517606};
CC -!- ACTIVITY REGULATION: Activated by phosphatidylserine and tumor necrosis
CC factor (TNF). Inhibited by scyphostatin. {ECO:0000269|PubMed:16517606}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC pH dependence:
CC Optimum pH is 7.0. {ECO:0000269|PubMed:16517606};
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:16517606, ECO:0000269|PubMed:18505924,
CC ECO:0000269|PubMed:31495489}; Single-pass membrane protein
CC {ECO:0000255}. Golgi apparatus membrane {ECO:0000269|PubMed:16517606};
CC Single-pass membrane protein {ECO:0000255}. Nucleus envelope
CC {ECO:0000269|PubMed:31495489}. Cell membrane, sarcolemma
CC {ECO:0000250|UniProtKB:Q6ZPR5}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=10;
CC Name=1; Synonyms=nSMase3a {ECO:0000303|PubMed:25180167};
CC IsoId=Q9NXE4-1; Sequence=Displayed;
CC Name=2; Synonyms=nSMase3b {ECO:0000303|PubMed:25180167};
CC IsoId=Q9NXE4-2; Sequence=VSP_022481;
CC Name=3;
CC IsoId=Q9NXE4-3; Sequence=VSP_022480;
CC Name=4;
CC IsoId=Q9NXE4-4; Sequence=VSP_022482;
CC Name=5;
CC IsoId=Q9NXE4-5; Sequence=VSP_022479, VSP_022483;
CC Name=6;
CC IsoId=Q9NXE4-6; Sequence=VSP_044495, VSP_022481;
CC Name=7;
CC IsoId=Q9NXE4-7; Sequence=VSP_054382, VSP_054385;
CC Name=8;
CC IsoId=Q9NXE4-8; Sequence=VSP_044495, VSP_054386, VSP_022481;
CC Name=9;
CC IsoId=Q9NXE4-9; Sequence=VSP_054383, VSP_054384;
CC Name=10;
CC IsoId=Q9NXE4-10; Sequence=VSP_055343, VSP_022481;
CC -!- TISSUE SPECIFICITY: Widely expressed, with highest levels in heart and
CC skeletal muscle. {ECO:0000269|PubMed:16517606,
CC ECO:0000269|PubMed:18505924, ECO:0000269|PubMed:25180167}.
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 -!- INDUCTION: Expression is induced by DNA-damage and TNF.
CC {ECO:0000269|PubMed:18505924}.
CC -!- DISEASE: Neurodevelopmental disorder with microcephaly, arthrogryposis,
CC and structural brain anomalies (NEDMABA) [MIM:618622]: An autosomal
CC recessive disorder characterized by severe global developmental delay,
CC severely impaired intellectual development with poor or absent speech,
CC severe encephalopathy, microcephaly with simplified gyral pattern,
CC hypomyelination, thin corpus callosum, mild cerebellar hypoplasia,
CC brainstem hypoplasia, congenital arthrogryposis, dysmorphic features,
CC and respiratory problems often leading to early demise.
CC {ECO:0000269|PubMed:31495489}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAY14883.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAA91070.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAA91368.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAA91567.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAA92656.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; EU367941; ACA48221.1; -; mRNA.
DR EMBL; AB037839; BAA92656.1; ALT_INIT; mRNA.
DR EMBL; AK000304; BAA91070.1; ALT_INIT; mRNA.
DR EMBL; AK000763; BAA91368.1; ALT_INIT; mRNA.
DR EMBL; AK001227; BAA91567.1; ALT_INIT; mRNA.
DR EMBL; AK126920; BAC86751.1; -; mRNA.
DR EMBL; AK297257; BAG59735.1; -; mRNA.
DR EMBL; AK298609; BAG60793.1; -; mRNA.
DR EMBL; AK299185; BAG61230.1; -; mRNA.
DR EMBL; AK303427; BAG64478.1; -; mRNA.
DR EMBL; AK301576; BAG63069.1; -; mRNA.
DR EMBL; AC018804; AAY14883.1; ALT_INIT; Genomic_DNA.
DR EMBL; CH471263; EAW55600.1; -; Genomic_DNA.
DR EMBL; BC064947; AAH64947.1; -; mRNA.
DR EMBL; AL136737; CAB66671.2; -; mRNA.
DR EMBL; CR533550; CAG38581.1; -; mRNA.
DR CCDS; CCDS2156.2; -. [Q9NXE4-2]
DR CCDS; CCDS54398.1; -. [Q9NXE4-6]
DR RefSeq; NP_001164554.1; NM_001171083.2. [Q9NXE4-6]
DR RefSeq; NP_060221.2; NM_017751.4. [Q9NXE4-2]
DR RefSeq; NP_060421.2; NM_017951.4. [Q9NXE4-1]
DR RefSeq; XP_011509747.1; XM_011511445.2. [Q9NXE4-3]
DR RefSeq; XP_016859937.1; XM_017004448.1. [Q9NXE4-7]
DR RefSeq; XP_016859938.1; XM_017004449.1.
DR AlphaFoldDB; Q9NXE4; -.
DR BioGRID; 120766; 179.
DR IntAct; Q9NXE4; 37.
DR MINT; Q9NXE4; -.
DR STRING; 9606.ENSP00000386531; -.
DR DrugBank; DB00144; Phosphatidyl serine.
DR GlyGen; Q9NXE4; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q9NXE4; -.
DR PhosphoSitePlus; Q9NXE4; -.
DR SwissPalm; Q9NXE4; -.
DR BioMuta; SMPD4; -.
DR DMDM; 124015179; -.
DR EPD; Q9NXE4; -.
DR jPOST; Q9NXE4; -.
DR MassIVE; Q9NXE4; -.
DR MaxQB; Q9NXE4; -.
DR PaxDb; Q9NXE4; -.
DR PeptideAtlas; Q9NXE4; -.
DR PRIDE; Q9NXE4; -.
DR ProteomicsDB; 17945; -.
DR ProteomicsDB; 4578; -.
DR ProteomicsDB; 4839; -.
DR ProteomicsDB; 5350; -.
DR ProteomicsDB; 5684; -.
DR ProteomicsDB; 83079; -. [Q9NXE4-1]
DR ProteomicsDB; 83080; -. [Q9NXE4-2]
DR ProteomicsDB; 83081; -. [Q9NXE4-3]
DR ProteomicsDB; 83082; -. [Q9NXE4-4]
DR ProteomicsDB; 83083; -. [Q9NXE4-5]
DR Antibodypedia; 56085; 89 antibodies from 20 providers.
DR DNASU; 55627; -.
DR Ensembl; ENST00000351288.10; ENSP00000259217.8; ENSG00000136699.20. [Q9NXE4-2]
DR Ensembl; ENST00000409031.5; ENSP00000386531.1; ENSG00000136699.20. [Q9NXE4-1]
DR Ensembl; ENST00000431183.6; ENSP00000405187.2; ENSG00000136699.20. [Q9NXE4-6]
DR GeneID; 55627; -.
DR KEGG; hsa:55627; -.
DR UCSC; uc002tqq.3; human.
DR UCSC; uc010zab.3; human. [Q9NXE4-1]
DR CTD; 55627; -.
DR DisGeNET; 55627; -.
DR GeneCards; SMPD4; -.
DR HGNC; HGNC:32949; SMPD4.
DR HPA; ENSG00000136699; Low tissue specificity.
DR MalaCards; SMPD4; -.
DR MIM; 610457; gene.
DR MIM; 618622; phenotype.
DR neXtProt; NX_Q9NXE4; -.
DR OpenTargets; ENSG00000136699; -.
DR PharmGKB; PA145148067; -.
DR VEuPathDB; HostDB:ENSG00000136699; -.
DR eggNOG; KOG4396; Eukaryota.
DR GeneTree; ENSGT00390000006044; -.
DR InParanoid; Q9NXE4; -.
DR OMA; AYAWRSE; -.
DR OrthoDB; 470341at2759; -.
DR PhylomeDB; Q9NXE4; -.
DR TreeFam; TF324409; -.
DR BRENDA; 3.1.4.12; 2681.
DR PathwayCommons; Q9NXE4; -.
DR Reactome; R-HSA-1660662; Glycosphingolipid metabolism.
DR SignaLink; Q9NXE4; -.
DR BioGRID-ORCS; 55627; 15 hits in 1077 CRISPR screens.
DR ChiTaRS; SMPD4; human.
DR GeneWiki; SMPD4; -.
DR GenomeRNAi; 55627; -.
DR Pharos; Q9NXE4; Tbio.
DR PRO; PR:Q9NXE4; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; Q9NXE4; protein.
DR Bgee; ENSG00000136699; Expressed in pituitary gland and 94 other tissues.
DR ExpressionAtlas; Q9NXE4; baseline and differential.
DR Genevisible; Q9NXE4; HS.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0005794; C:Golgi apparatus; IDA: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; ISS:UniProtKB.
DR GO; GO:0005640; C:nuclear outer membrane; IDA:UniProtKB.
DR GO; GO:0042383; C:sarcolemma; ISS:UniProtKB.
DR GO; GO:0005802; C:trans-Golgi network; IDA:HGNC-UCL.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004767; F:sphingomyelin phosphodiesterase activity; IEA:UniProtKB-EC.
DR GO; GO:0050290; F:sphingomyelin phosphodiesterase D activity; IDA:UniProtKB.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IDA:BHF-UCL.
DR GO; GO:0046513; P:ceramide biosynthetic process; IDA:UniProtKB.
DR GO; GO:0007029; P:endoplasmic reticulum organization; IMP:UniProtKB.
DR GO; GO:0046475; P:glycerophospholipid catabolic process; IDA:BHF-UCL.
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; Disease variant;
KW Endoplasmic reticulum; Golgi apparatus; Hydrolase; Intellectual disability;
KW Lipid metabolism; Magnesium; Membrane; Metal-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..866
FT /note="Sphingomyelin phosphodiesterase 4"
FT /id="PRO_0000273163"
FT TRANSMEM 822..842
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:18505924"
FT MOD_RES 169
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:23186163"
FT MOD_RES 285
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q6ZPR5"
FT MOD_RES 708
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:18691976"
FT MOD_RES 792
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VAR_SEQ 1..307
FT /note="Missing (in isoform 10)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_055343"
FT VAR_SEQ 1..135
FT /note="MTTFGAVAEWRLPSLRRATLWIPQWFAKKAIFNSPLEAAMAFPHLQQPSFLL
FT ASLKADSINKPFAQQCQDLVKVIEDFPAKELHTIFPWLVESIFGSLDGVLVGWNLRCLQ
FT GRVNPVEYSIVMEFLDPGGPMMKL -> MQTPPPTRSGGQKLCSRFLLKCGFITIPWRC
FT IKKCSPLMPSWRFCTTDSVSPAPSTAPPNPASRPSTPTKSLGNRGSDARGFYWAEFSSG
FT CVQDEE (in isoform 7)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_054382"
FT VAR_SEQ 1..131
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_022480"
FT VAR_SEQ 1..79
FT /note="MTTFGAVAEWRLPSLRRATLWIPQWFAKKAIFNSPLEAAMAFPHLQQPSFLL
FT ASLKADSINKPFAQQCQDLVKVIEDFP -> MQTPPPTRSGGQKLCSRFLLKCGFITIP
FT WRCIKKCSPLMP (in isoform 9)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_054383"
FT VAR_SEQ 40..468
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_022479"
FT VAR_SEQ 80..404
FT /note="Missing (in isoform 9)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_054384"
FT VAR_SEQ 82..154
FT /note="Missing (in isoform 6 and isoform 8)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_044495"
FT VAR_SEQ 136..355
FT /note="Missing (in isoform 7)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_054385"
FT VAR_SEQ 155..303
FT /note="Missing (in isoform 8)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_054386"
FT VAR_SEQ 328..356
FT /note="Missing (in isoform 2, isoform 6, isoform 8 and
FT isoform 10)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_022481"
FT VAR_SEQ 404
FT /note="K -> KRMGLNLPEVPSALPRRSQPSLMGALGSSVSRASLLGKQQVTLPIPC
FT (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_022482"
FT VAR_SEQ 469..523
FT /note="WAPFVQENLLMYTKLFVGFLNRALRTDLVSPKHALMVFRVAKVFAQPNLAEM
FT IQK -> MSATYCVGDAARQGLRRTPLGHGSPDTSETPQNPKGSSRVLCLREVGARFVS
FT CLL (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_022483"
FT VARIANT 67..866
FT /note="Missing (in NEDMABA)"
FT /evidence="ECO:0000269|PubMed:31495489"
FT /id="VAR_083329"
FT VARIANT 124..866
FT /note="Missing (in NEDMABA)"
FT /evidence="ECO:0000269|PubMed:31495489"
FT /id="VAR_083330"
FT VARIANT 231
FT /note="L -> P (in NEDMABA)"
FT /evidence="ECO:0000269|PubMed:31495489"
FT /id="VAR_083331"
FT VARIANT 446
FT /note="P -> L (in NEDMABA; unknown pathological
FT significance; dbSNP:rs747433356)"
FT /evidence="ECO:0000269|PubMed:31495489"
FT /id="VAR_083332"
FT VARIANT 661
FT /note="A -> V (in NEDMABA; unknown pathological
FT significance; dbSNP:rs1461194496)"
FT /evidence="ECO:0000269|PubMed:31495489"
FT /id="VAR_083333"
FT VARIANT 761..866
FT /note="Missing (in NEDMABA; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:31495489"
FT /id="VAR_083334"
FT MUTAGEN 862..865
FT /note="KLHQ->AAAA: No effect on endoplasmic reticulum
FT location."
FT /evidence="ECO:0000269|PubMed:18505924"
FT CONFLICT 203
FT /note="S -> G (in Ref. 3; BAG61230)"
FT /evidence="ECO:0000305"
FT CONFLICT 579
FT /note="C -> R (in Ref. 3; BAA91567)"
FT /evidence="ECO:0000305"
FT CONFLICT 731
FT /note="E -> K (in Ref. 3; BAA91368)"
FT /evidence="ECO:0000305"
FT CONFLICT 732
FT /note="L -> Q (in Ref. 3; BAA91567)"
FT /evidence="ECO:0000305"
FT CONFLICT 742
FT /note="S -> G (in Ref. 3; BAC86751)"
FT /evidence="ECO:0000305"
FT CONFLICT 862
FT /note="K -> E (in Ref. 3; BAG61230)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 866 AA; 97810 MW; 3D7C615AAF733865 CRC64;
MTTFGAVAEW RLPSLRRATL WIPQWFAKKA IFNSPLEAAM AFPHLQQPSF LLASLKADSI
NKPFAQQCQD LVKVIEDFPA KELHTIFPWL VESIFGSLDG VLVGWNLRCL QGRVNPVEYS
IVMEFLDPGG PMMKLVYKLQ AEDYKFDFPV SYLPGPVKAS IQECILPDSP LYHNKVQFTP
TGGLGLNLAL NPFEYYIFFF ALSLITQKPL PVSLHVRTSD CAYFILVDRY LSWFLPTEGS
VPPPLSSSPG GTSPSPPPRT PAIPFASYGL HHTSLLKRHI SHQTSVNADP ASHEIWRSET
LLQVFVEMWL HHYSLEMYQK MQSPHAKLEV LHYRLSVSSA LYSPAQPSLQ ALHAYQESFT
PTEEHVLVVR LLLKHLHAFA NSLKPEQASP SAHSHATSPL EEFKRAAVPR FVQQKLYLFL
QHCFGHWPLD ASFRAVLEMW LSYLQPWRYA PDKQAPGSDS QPRCVSEKWA PFVQENLLMY
TKLFVGFLNR ALRTDLVSPK HALMVFRVAK VFAQPNLAEM IQKGEQLFLE PELVIPHRQH
RLFTAPTFTG SFLSPWPPAV TDASFKVKSH VYSLEGQDCK YTPMFGPEAR TLVLRLAQLI
TQAKHTAKSI SDQCAESPAG HSFLSWLGFS SMDTNGSYTA NDLDEMGQDS VRKTDEYLEK
ALEYLRQIFR LSEAQLRQFT LALGTTQDEN GKKQLPDCIV GEDGLILTPL GRYQIINGLR
RFEIEYQGDP ELQPIRSYEI ASLVRTLFRL SSAINHRFAG QMAALCSRDD FLGSFCRYHL
TEPGLASRHL LSPVGRRQVA GHTRGPRLSL RFLGSYRTLV SLLLAFFVAS LFCVGPLPCT
LLLTLGYVLY ASAMTLLTER GKLHQP
