ISC1_YEAST
ID ISC1_YEAST Reviewed; 477 AA.
AC P40015; D3DLR7;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1995, sequence version 1.
DT 03-AUG-2022, entry version 169.
DE RecName: Full=Inositol phosphosphingolipids phospholipase C {ECO:0000303|PubMed:11006294};
DE Short=IPS phospholipase C {ECO:0000303|PubMed:11006294};
DE Short=IPS-PLC {ECO:0000303|PubMed:11006294};
DE EC=3.1.4.- {ECO:0000269|PubMed:11006294};
DE AltName: Full=Neutral sphingomyelinase {ECO:0000303|PubMed:11006294};
DE Short=N-SMase {ECO:0000303|PubMed:11006294};
DE Short=nSMase {ECO:0000303|PubMed:11006294};
GN Name=ISC1 {ECO:0000303|PubMed:11006294}; OrderedLocusNames=YER019W;
OS Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Saccharomycotina; Saccharomycetes;
OC Saccharomycetales; Saccharomycetaceae; Saccharomyces.
OX NCBI_TaxID=559292;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 204508 / S288c;
RX PubMed=9169868;
RA Dietrich F.S., Mulligan J.T., Hennessy K.M., Yelton M.A., Allen E.,
RA Araujo R., Aviles E., Berno A., Brennan T., Carpenter J., Chen E.,
RA Cherry J.M., Chung E., Duncan M., Guzman E., Hartzell G., Hunicke-Smith S.,
RA Hyman R.W., Kayser A., Komp C., Lashkari D., Lew H., Lin D., Mosedale D.,
RA Nakahara K., Namath A., Norgren R., Oefner P., Oh C., Petel F.X.,
RA Roberts D., Sehl P., Schramm S., Shogren T., Smith V., Taylor P., Wei Y.,
RA Botstein D., Davis R.W.;
RT "The nucleotide sequence of Saccharomyces cerevisiae chromosome V.";
RL Nature 387:78-81(1997).
RN [2]
RP GENOME REANNOTATION.
RC STRAIN=ATCC 204508 / S288c;
RX PubMed=24374639; DOI=10.1534/g3.113.008995;
RA Engel S.R., Dietrich F.S., Fisk D.G., Binkley G., Balakrishnan R.,
RA Costanzo M.C., Dwight S.S., Hitz B.C., Karra K., Nash R.S., Weng S.,
RA Wong E.D., Lloyd P., Skrzypek M.S., Miyasato S.R., Simison M., Cherry J.M.;
RT "The reference genome sequence of Saccharomyces cerevisiae: Then and now.";
RL G3 (Bethesda) 4:389-398(2014).
RN [3]
RP FUNCTION, DISRUPTION PHENOTYPE, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL
RP PROPERTIES.
RX PubMed=11006294; DOI=10.1074/jbc.m007721200;
RA Sawai H., Okamoto Y., Luberto C., Mao C., Bielawska A., Domae N.,
RA Hannun Y.A.;
RT "Identification of ISC1 (YER019w) as inositol phosphosphingolipid
RT phospholipase C in Saccharomyces cerevisiae.";
RL J. Biol. Chem. 275:39793-39798(2000).
RN [4]
RP LEVEL OF PROTEIN EXPRESSION [LARGE SCALE ANALYSIS].
RX PubMed=14562106; DOI=10.1038/nature02046;
RA Ghaemmaghami S., Huh W.-K., Bower K., Howson R.W., Belle A., Dephoure N.,
RA O'Shea E.K., Weissman J.S.;
RT "Global analysis of protein expression in yeast.";
RL Nature 425:737-741(2003).
RN [5]
RP SUBCELLULAR LOCATION, AND ACTIVITY REGULATION.
RX PubMed=14699160; DOI=10.1074/jbc.m309586200;
RA Vaena de Avalos S., Okamoto Y., Hannun Y.A.;
RT "Activation and localization of inositol phosphosphingolipid phospholipase
RT C, Isc1p, to the mitochondria during growth of Saccharomyces cerevisiae.";
RL J. Biol. Chem. 279:11537-11545(2004).
RN [6]
RP TOPOLOGY [LARGE SCALE ANALYSIS].
RC STRAIN=ATCC 208353 / W303-1A;
RX PubMed=16847258; DOI=10.1073/pnas.0604075103;
RA Kim H., Melen K., Oesterberg M., von Heijne G.;
RT "A global topology map of the Saccharomyces cerevisiae membrane proteome.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:11142-11147(2006).
RN [7]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=17880915; DOI=10.1016/j.bbamem.2007.07.019;
RA Kitagaki H., Cowart L.A., Matmati N., Vaena de Avalos S., Novgorodov S.A.,
RA Zeidan Y.H., Bielawski J., Obeid L.M., Hannun Y.A.;
RT "Isc1 regulates sphingolipid metabolism in yeast mitochondria.";
RL Biochim. Biophys. Acta 1768:2849-2861(2007).
CC -!- FUNCTION: Responsible for the hydrolysis of the phosphosphingolipids
CC (IPS), inositol phosphorylceramide (IPC), mannosylinositol
CC phosphorylceramide (MIPC), and mannosyldiinositol phosphorylceramide
CC (M(IP)2C) (PubMed:11006294). Regulates sphingolipid metabolism in
CC mitochondria, especially the formation of alpha-hydroxylated very long
CC chain phytoceramides. The generated ceramides contribute to the normal
CC function of mitochondria (PubMed:17880915). Also active on
CC sphingomyelin (SM), but this activity is probably not physiologically
CC relevant (PubMed:11006294). {ECO:0000269|PubMed:11006294,
CC ECO:0000269|PubMed:17880915}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an N-acyl-(4R)-4-hydroxysphinganine-1-phosphoinositol + H2O =
CC 1D-myo-inositol 1-phosphate + an N-acyl-(4R)-4-hydroxysphinganine +
CC H(+); Xref=Rhea:RHEA:55688, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:31998, ChEBI:CHEBI:58433, ChEBI:CHEBI:64940;
CC Evidence={ECO:0000269|PubMed:11006294};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:55689;
CC Evidence={ECO:0000269|PubMed:11006294};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a mannosylinositol-1-phospho-N-acyl-sphingoid base + H2O = an
CC N-acyl-sphingoid base + H(+) + mannosylinositol-1-phosphate;
CC Xref=Rhea:RHEA:55696, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:64997, ChEBI:CHEBI:83273, ChEBI:CHEBI:139147;
CC Evidence={ECO:0000269|PubMed:11006294};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:55697;
CC Evidence={ECO:0000269|PubMed:11006294};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an inositol phosphomannosylinositol-1-phospho-N-acyl-(4R)-4-
CC hydroxysphinganine + H2O = an N-acyl-(4R)-4-hydroxysphinganine + H(+)
CC + mannosyldiinositol-1-phosphate; Xref=Rhea:RHEA:55700,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:31998,
CC ChEBI:CHEBI:139090, ChEBI:CHEBI:139148;
CC Evidence={ECO:0000269|PubMed:11006294};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:55701;
CC Evidence={ECO:0000269|PubMed:11006294};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC -!- ACTIVITY REGULATION: Activated through localization to mitochondria in
CC specific growth phases. {ECO:0000269|PubMed:14699160}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=35.37 uM for SM {ECO:0000269|PubMed:11006294};
CC KM=53.28 uM for IPC {ECO:0000269|PubMed:11006294};
CC KM=27.61 uM for MIPC {ECO:0000269|PubMed:11006294};
CC KM=28.65 uM for M(IP)2C {ECO:0000269|PubMed:11006294};
CC Vmax=9.2 nmol/h/ug enzyme toward SM {ECO:0000269|PubMed:11006294};
CC Vmax=2.7 nmol/h/ug enzyme toward IPC {ECO:0000269|PubMed:11006294};
CC Vmax=7.8 nmol/h/ug enzyme toward MIPC {ECO:0000269|PubMed:11006294};
CC Vmax=9.1 nmol/h/ug enzyme toward M(IP)2C
CC {ECO:0000269|PubMed:11006294};
CC -!- PATHWAY: Lipid metabolism; sphingolipid metabolism.
CC {ECO:0000269|PubMed:11006294}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:14699160}; Multi-pass membrane protein
CC {ECO:0000255}. Mitochondrion outer membrane
CC {ECO:0000269|PubMed:14699160, ECO:0000269|PubMed:17880915}; Multi-pass
CC membrane protein {ECO:0000255}. Note=Localization is regulated in a
CC growth-dependent manner. Predominantly in the ER during early growth
CC and becomes associated with mitochondria in late logarithmic growth.
CC {ECO:0000269|PubMed:14699160}.
CC -!- DISRUPTION PHENOTYPE: Eliminates endogenous IPS-PLC activities.
CC {ECO:0000269|PubMed:11006294}.
CC -!- MISCELLANEOUS: Present with 2170 molecules/cell in log phase SD medium.
CC {ECO:0000269|PubMed:14562106}.
CC -!- SIMILARITY: Belongs to the neutral sphingomyelinase family.
CC {ECO:0000305}.
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DR EMBL; U18778; AAB64552.1; -; Genomic_DNA.
DR EMBL; BK006939; DAA07671.1; -; Genomic_DNA.
DR PIR; S50477; S50477.
DR RefSeq; NP_010935.1; NM_001178910.1.
DR AlphaFoldDB; P40015; -.
DR BioGRID; 36752; 255.
DR DIP; DIP-5002N; -.
DR IntAct; P40015; 4.
DR STRING; 4932.YER019W; -.
DR SwissLipids; SLP:000001859; -.
DR iPTMnet; P40015; -.
DR MaxQB; P40015; -.
DR PaxDb; P40015; -.
DR PRIDE; P40015; -.
DR TopDownProteomics; P40015; -.
DR EnsemblFungi; YER019W_mRNA; YER019W; YER019W.
DR GeneID; 856739; -.
DR KEGG; sce:YER019W; -.
DR SGD; S000000821; ISC1.
DR VEuPathDB; FungiDB:YER019W; -.
DR eggNOG; KOG3873; Eukaryota.
DR GeneTree; ENSGT00390000009166; -.
DR HOGENOM; CLU_034001_5_0_1; -.
DR InParanoid; P40015; -.
DR OMA; WDIESAR; -.
DR BioCyc; MetaCyc:YER019W-MON; -.
DR BioCyc; YEAST:YER019W-MON; -.
DR Reactome; R-SCE-1660662; Glycosphingolipid metabolism.
DR UniPathway; UPA00222; -.
DR PRO; PR:P40015; -.
DR Proteomes; UP000002311; Chromosome V.
DR RNAct; P40015; protein.
DR GO; GO:0071944; C:cell periphery; HDA:SGD.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:SGD.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0031307; C:integral component of mitochondrial outer membrane; IDA:SGD.
DR GO; GO:0016020; C:membrane; IBA:GO_Central.
DR GO; GO:0005739; C:mitochondrion; IDA:SGD.
DR GO; GO:0052712; F:inositol phosphosphingolipid phospholipase activity; IDA:SGD.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004620; F:phospholipase activity; IBA:GO_Central.
DR GO; GO:0004767; F:sphingomyelin phosphodiesterase activity; IEA:InterPro.
DR GO; GO:0046513; P:ceramide biosynthetic process; IMP:SGD.
DR GO; GO:0090266; P:regulation of mitotic cell cycle spindle assembly checkpoint; IMP:SGD.
DR GO; GO:0009651; P:response to salt stress; IMP:SGD.
DR GO; GO:0030149; P:sphingolipid catabolic process; IDA:SGD.
DR Gene3D; 3.60.10.10; -; 1.
DR InterPro; IPR036691; Endo/exonu/phosph_ase_sf.
DR InterPro; IPR005135; Endo/exonuclease/phosphatase.
DR InterPro; IPR038772; SMPD2-like.
DR PANTHER; PTHR12393; PTHR12393; 1.
DR Pfam; PF03372; Exo_endo_phos; 1.
DR SUPFAM; SSF56219; SSF56219; 1.
PE 1: Evidence at protein level;
KW Endoplasmic reticulum; Hydrolase; Lipid metabolism; Magnesium; Membrane;
KW Metal-binding; Mitochondrion; Mitochondrion outer membrane;
KW Reference proteome; Sphingolipid metabolism; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..477
FT /note="Inositol phosphosphingolipids phospholipase C"
FT /id="PRO_0000075695"
FT TOPO_DOM 1..398
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:16847258"
FT TRANSMEM 399..417
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 418..424
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000305|PubMed:16847258"
FT TRANSMEM 425..449
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 450..477
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:16847258"
FT ACT_SITE 334
FT /note="Proton acceptor"
FT /evidence="ECO:0000250"
FT BINDING 100
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250"
FT SITE 233
FT /note="Important for substrate recognition"
FT /evidence="ECO:0000250"
SQ SEQUENCE 477 AA; 53940 MW; 0670FD303FEB8EFF CRC64;
MYNRKDRDVH ERKEDGQSEF EALNGTNAIM SDNSKAYSIK FLTFNTWGLK YVSKHRKERL
RAIADKLAGH SMLTPISDEL LPNGGDSNEN EDYDVIALQE IWCVEDWKYL ASACASKYPY
QRLFHSGILT GPGLAILSKV PIESTFLYRF PINGRPSAVF RGDWYVGKSI AITVLNTGTR
PIAIMNSHMH APYAKQGDAA YLCHRSCQAW DFSRLIKLYR QAGYAVIVVG DLNSRPGSLP
HKFLTQEAGL VDSWEQLHGK QDLAVIARLS PLQQLLKGCT TCDSLLNTWR AQRQPDEACR
LDYALIDPDF LQTVDAGVRF TERIPHLDCS VSDHFAYSCT LNIVPQGTES RPSTSVKRAK
THDRELILQR YSNYETMIEC IHTYLKTAQR QKFFRGLHFW ASILLLIASL VVTTFTANKA
GWSSIFWVLF AIAVSISGTI DGAISFLFGR SEIRALIEVE QEVLDAEHHL QTFLSEK
