ID   ERG1_HUMAN              Reviewed;         574 AA.
AC   Q14534; Q9UEK6; Q9UNR6;
DT   01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT   18-MAY-2010, sequence version 3.
DT   27-MAR-2024, entry version 193.
DE   RecName: Full=Squalene monooxygenase;
DE            EC=1.14.14.17 {ECO:0000269|PubMed:10666321, ECO:0000269|PubMed:30626872};
DE   AltName: Full=Squalene epoxidase {ECO:0000303|PubMed:9286711};
DE            Short=SE;
GN   Name=SQLE; Synonyms=ERG1;
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].
RX   PubMed=9286711; DOI=10.1006/geno.1997.4825;
RA   Nagai M., Sakakibara J., Wakui K., Fukushima Y., Igarashi S., Tsuji S.,
RA   Arakawa M., Ono T.;
RT   "Localization of the squalene epoxidase gene (SQLE) to human chromosome
RT   region 8q24.1.";
RL   Genomics 44:141-143(1997).
RN   [2] {ECO:0000312|EMBL:AAD10823.1}
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, ACTIVITY
RP   REGULATION, COFACTOR, AND PATHWAY.
RC   TISSUE=Liver {ECO:0000312|EMBL:AAD10823.1};
RX   PubMed=10666321; DOI=10.1006/abbi.1999.1629;
RA   Laden B.P., Tang Y., Porter T.D.;
RT   "Cloning, heterologous expression, and enzymological characterization of
RT   human squalene monooxygenase.";
RL   Arch. Biochem. Biophys. 374:381-388(2000).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Ovary {ECO:0000312|EMBL:BAG36182.1};
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 MRNA].
RC   TISSUE=Colon endothelium;
RX   PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA   Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA   Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA   Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA   Wiemann S., Schupp I.;
RT   "The full-ORF clone resource of the German cDNA consortium.";
RL   BMC Genomics 8:399-399(2007).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16421571; DOI=10.1038/nature04406;
RA   Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M.,
RA   Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L.,
RA   Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S.,
RA   Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A.,
RA   Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III,
RA   Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K.,
RA   Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA   Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA   Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B.,
RA   O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K.,
RA   Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L.,
RA   Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G.,
RA   Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W.,
RA   Platzer M., Shimizu N., Lander E.S.;
RT   "DNA sequence and analysis of human chromosome 8.";
RL   Nature 439:331-335(2006).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.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   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Colon {ECO:0000312|EMBL:AAH17033.1};
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   [8]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 187-535.
RC   TISSUE=Liver;
RX   PubMed=8626488; DOI=10.1074/jbc.271.14.8053;
RA   Nakamura Y., Sakakibara J., Izumi T., Shibata A., Ono T.;
RT   "Transcriptional regulation of squalene epoxidase by sterols and inhibitors
RT   in HeLa cells.";
RL   J. Biol. Chem. 271:8053-8056(1996).
RN   [9]
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   [10]
RP   DOMAIN, INTERACTION WITH MARCHF6, UBIQUITINATION, AND PATHWAY.
RX   PubMed=24449766; DOI=10.1128/mcb.01140-13;
RA   Zelcer N., Sharpe L.J., Loregger A., Kristiana I., Cook E.C., Phan L.,
RA   Stevenson J., Brown A.J.;
RT   "The E3 ubiquitin ligase MARCH6 degrades squalene monooxygenase and affects
RT   3-hydroxy-3-methyl-glutaryl coenzyme A reductase and the cholesterol
RT   synthesis pathway.";
RL   Mol. Cell. Biol. 34:1262-1270(2014).
RN   [11]
RP   SUBCELLULAR LOCATION, TOPOLOGY, AND DOMAIN.
RX   PubMed=26434806; DOI=10.1074/jbc.m115.675181;
RA   Howe V., Chua N.K., Stevenson J., Brown A.J.;
RT   "The Regulatory Domain of Squalene Monooxygenase Contains a Re-entrant Loop
RT   and Senses Cholesterol via a Conformational Change.";
RL   J. Biol. Chem. 290:27533-27544(2015).
RN   [12]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=25944712; DOI=10.1002/pmic.201400617;
RA   Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA   Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT   "N-terminome analysis of the human mitochondrial proteome.";
RL   Proteomics 15:2519-2524(2015).
RN   [13]
RP   DOMAIN, SUBCELLULAR LOCATION, TOPOLOGY, AND MUTAGENESIS OF PHE-35; SER-37;
RP   62-GLN--LEU-73; LEU-65 AND ILE-69.
RX   PubMed=28972164; DOI=10.1074/jbc.m117.794230;
RA   Chua N.K., Howe V., Jatana N., Thukral L., Brown A.J.;
RT   "A conserved degron containing an amphipathic helix regulates the
RT   cholesterol-mediated turnover of human squalene monooxygenase, a rate-
RT   limiting enzyme in cholesterol synthesis.";
RL   J. Biol. Chem. 292:19959-19973(2017).
RN   [14]
RP   INTERACTION WITH SMIM22.
RX   PubMed=29765154; DOI=10.1038/s41388-018-0281-5;
RA   Polycarpou-Schwarz M., Gross M., Mestdagh P., Schott J., Grund S.E.,
RA   Hildenbrand C., Rom J., Aulmann S., Sinn H.P., Vandesompele J.,
RA   Diederichs S.;
RT   "The cancer-associated microprotein CASIMO1 controls cell proliferation and
RT   interacts with squalene epoxidase modulating lipid droplet formation.";
RL   Oncogene 37:4750-4768(2018).
RN   [15] {ECO:0007744|PDB:6C6N, ECO:0007744|PDB:6C6P, ECO:0007744|PDB:6C6R}
RP   X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 118-574 IN COMPLEXES WITH FAD AND
RP   SYNTHETIC INHIBITORS, FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL
RP   PROPERTIES, COFACTOR, PATHWAY, TISSUE SPECIFICITY, SUBCELLULAR LOCATION,
RP   ACTIVITY REGULATION, MUTAGENESIS OF TYR-195, AND DOMAIN.
RX   PubMed=30626872; DOI=10.1038/s41467-018-07928-x;
RA   Padyana A.K., Gross S., Jin L., Cianchetta G., Narayanaswamy R., Wang F.,
RA   Wang R., Fang C., Lv X., Biller S.A., Dang L., Mahoney C.E., Nagaraja N.,
RA   Pirman D., Sui Z., Popovici-Muller J., Smolen G.A.;
RT   "Structure and inhibition mechanism of the catalytic domain of human
RT   squalene epoxidase.";
RL   Nat. Commun. 10:97-97(2019).
CC   -!- FUNCTION: Catalyzes the stereospecific oxidation of squalene to
CC       (S)-2,3-epoxysqualene, and is considered to be a rate-limiting enzyme
CC       in steroid biosynthesis. {ECO:0000269|PubMed:10666321,
CC       ECO:0000269|PubMed:30626872}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=O2 + reduced [NADPH--hemoprotein reductase] + squalene = (S)-
CC         2,3-epoxysqualene + H(+) + H2O + oxidized [NADPH--hemoprotein
CC         reductase]; Xref=Rhea:RHEA:25282, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC         COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:15440, ChEBI:CHEBI:15441, ChEBI:CHEBI:57618,
CC         ChEBI:CHEBI:58210; EC=1.14.14.17;
CC         Evidence={ECO:0000269|PubMed:10666321, ECO:0000269|PubMed:30626872};
CC   -!- COFACTOR:
CC       Name=FAD; Xref=ChEBI:CHEBI:57692;
CC         Evidence={ECO:0000269|PubMed:10666321, ECO:0000269|PubMed:30626872};
CC   -!- ACTIVITY REGULATION: Inhibited by NB-598 ((E)N-ethyl-N-(6,6-dimethyl-2-
CC       hepten-4-ynyl)-3-[(3,3'-bi-thiophen-5-yl)methoxy]benzene-methanamine).
CC       Contrary to fungal enzymes, the mammalian enzyme is only slightly
CC       inhibited by terbinafine (PubMed:30626872). Inhibited by tellurite,
CC       tellurium dioxide, selenite, and selenium dioxide (PubMed:10666321).
CC       {ECO:0000269|PubMed:10666321, ECO:0000269|PubMed:30626872}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=2.9 uM for squalene {ECO:0000269|PubMed:30626872};
CC         KM=9.6 uM for FAD {ECO:0000269|PubMed:30626872};
CC   -!- PATHWAY: Terpene metabolism; lanosterol biosynthesis; lanosterol from
CC       farnesyl diphosphate: step 2/3. {ECO:0000269|PubMed:24449766,
CC       ECO:0000305|PubMed:10666321, ECO:0000305|PubMed:30626872}.
CC   -!- SUBUNIT: Interacts (via N-terminal domain) with MARCHF6. Interacts with
CC       SMIM22; this interaction modulates lipid droplet formation
CC       (PubMed:29765154). {ECO:0000269|PubMed:24449766,
CC       ECO:0000269|PubMed:29765154}.
CC   -!- INTERACTION:
CC       Q14534; Q96BA8: CREB3L1; NbExp=3; IntAct=EBI-3905171, EBI-6942903;
CC       Q14534; Q9H6H4: REEP4; NbExp=3; IntAct=EBI-3905171, EBI-7545592;
CC       Q14534; Q9NUH8: TMEM14B; NbExp=3; IntAct=EBI-3905171, EBI-8638294;
CC   -!- SUBCELLULAR LOCATION: Microsome membrane {ECO:0000269|PubMed:26434806,
CC       ECO:0000269|PubMed:28972164, ECO:0000269|PubMed:30626872}; Peripheral
CC       membrane protein {ECO:0000269|PubMed:26434806,
CC       ECO:0000269|PubMed:28972164}. Endoplasmic reticulum membrane
CC       {ECO:0000305|PubMed:26434806}; Peripheral membrane protein
CC       {ECO:0000269|PubMed:26434806, ECO:0000269|PubMed:28972164}.
CC   -!- TISSUE SPECIFICITY: Detected in liver (at protein level).
CC       {ECO:0000269|PubMed:30626872}.
CC   -!- DOMAIN: The C-terminal hydrophobic region contains two helices that
CC       mediate interaction with membranes. Contrary to predictions, this
CC       region does not contain transmembrane helices.
CC       {ECO:0000269|PubMed:30626872}.
CC   -!- DOMAIN: The N-terminal region mediates interaction with MARCHF6,
CC       leading to SQLE ubiquitination and proteasomal degradation when
CC       cholosterol levels are high (PubMed:24449766, PubMed:26434806,
CC       PubMed:28972164). The first part of the N-terminal region contains a
CC       hydrophobic region that inserts into the membrane; contrary to
CC       predictions, there are no transmembrane helices (PubMed:26434806). The
CC       second part contains a region that can form an amphipathic region that
CC       associates with membranes. This region is ejected from the membrane by
CC       high cholesterol levels and becomes disordered in an aqueous
CC       environment. This is critical for cholesterol-dependent proteasomal
CC       degradation. Additional parts of the N-terminal region are predicted to
CC       be disordered and contribute to flagging the protein for proteasomal
CC       degradation already under basal conditions (PubMed:28972164).
CC       {ECO:0000269|PubMed:24449766, ECO:0000269|PubMed:26434806,
CC       ECO:0000269|PubMed:28972164}.
CC   -!- PTM: Ubiquitinated by MARCHF6 in response to high cholesterol levels in
CC       intracellular membranes, leading to proteasomal degradation.
CC       {ECO:0000269|PubMed:24449766}.
CC   -!- SIMILARITY: Belongs to the squalene monooxygenase family.
CC       {ECO:0000305}.
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DR   EMBL; D78130; BAA22372.1; -; mRNA.
DR   EMBL; AF098865; AAD10823.1; -; mRNA.
DR   EMBL; AK313384; BAG36182.1; -; mRNA.
DR   EMBL; BX647400; -; NOT_ANNOTATED_CDS; mRNA.
DR   EMBL; AC009908; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471060; EAW92079.1; -; Genomic_DNA.
DR   EMBL; BC017033; AAH17033.1; -; mRNA.
DR   EMBL; FJ695197; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; D78129; BAA11209.1; -; mRNA.
DR   CCDS; CCDS47918.1; -.
DR   RefSeq; NP_003120.2; NM_003129.3.
DR   PDB; 6C6N; X-ray; 2.30 A; A/B=118-574.
DR   PDB; 6C6P; X-ray; 2.50 A; A/B=118-574.
DR   PDB; 6C6R; X-ray; 3.00 A; A/B=118-574.
DR   PDBsum; 6C6N; -.
DR   PDBsum; 6C6P; -.
DR   PDBsum; 6C6R; -.
DR   AlphaFoldDB; Q14534; -.
DR   SMR; Q14534; -.
DR   BioGRID; 112591; 50.
DR   IntAct; Q14534; 21.
DR   MINT; Q14534; -.
DR   STRING; 9606.ENSP00000265896; -.
DR   BindingDB; Q14534; -.
DR   ChEMBL; CHEMBL3592; -.
DR   DrugBank; DB01091; Butenafine.
DR   DrugBank; DB08846; Ellagic acid.
DR   DrugBank; DB00735; Naftifine.
DR   DrugBank; DB00857; Terbinafine.
DR   DrugCentral; Q14534; -.
DR   GuidetoPHARMACOLOGY; 2433; -.
DR   SwissLipids; SLP:000001243; -.
DR   iPTMnet; Q14534; -.
DR   PhosphoSitePlus; Q14534; -.
DR   SwissPalm; Q14534; -.
DR   BioMuta; SQLE; -.
DR   DMDM; 296439362; -.
DR   EPD; Q14534; -.
DR   jPOST; Q14534; -.
DR   MassIVE; Q14534; -.
DR   PaxDb; 9606-ENSP00000265896; -.
DR   PeptideAtlas; Q14534; -.
DR   ProteomicsDB; 60034; -.
DR   Pumba; Q14534; -.
DR   Antibodypedia; 27121; 190 antibodies from 27 providers.
DR   DNASU; 6713; -.
DR   Ensembl; ENST00000265896.10; ENSP00000265896.5; ENSG00000104549.12.
DR   GeneID; 6713; -.
DR   KEGG; hsa:6713; -.
DR   MANE-Select; ENST00000265896.10; ENSP00000265896.5; NM_003129.4; NP_003120.2.
DR   UCSC; uc011liq.3; human.
DR   AGR; HGNC:11279; -.
DR   CTD; 6713; -.
DR   DisGeNET; 6713; -.
DR   GeneCards; SQLE; -.
DR   HGNC; HGNC:11279; SQLE.
DR   HPA; ENSG00000104549; Low tissue specificity.
DR   MIM; 602019; gene.
DR   neXtProt; NX_Q14534; -.
DR   OpenTargets; ENSG00000104549; -.
DR   PharmGKB; PA36108; -.
DR   VEuPathDB; HostDB:ENSG00000104549; -.
DR   eggNOG; KOG1298; Eukaryota.
DR   GeneTree; ENSGT00390000011759; -.
DR   InParanoid; Q14534; -.
DR   OMA; AKRTFYW; -.
DR   OrthoDB; 148348at2759; -.
DR   PhylomeDB; Q14534; -.
DR   TreeFam; TF331056; -.
DR   BioCyc; MetaCyc:HS02595-MONOMER; -.
DR   BRENDA; 1.14.14.17; 2681.
DR   PathwayCommons; Q14534; -.
DR   Reactome; R-HSA-191273; Cholesterol biosynthesis.
DR   Reactome; R-HSA-2426168; Activation of gene expression by SREBF (SREBP).
DR   SABIO-RK; Q14534; -.
DR   SignaLink; Q14534; -.
DR   SIGNOR; Q14534; -.
DR   UniPathway; UPA00767; UER00752.
DR   BioGRID-ORCS; 6713; 61 hits in 1181 CRISPR screens.
DR   ChiTaRS; SQLE; human.
DR   GeneWiki; Squalene_monooxygenase; -.
DR   GenomeRNAi; 6713; -.
DR   Pharos; Q14534; Tchem.
DR   PRO; PR:Q14534; -.
DR   Proteomes; UP000005640; Chromosome 8.
DR   RNAct; Q14534; Protein.
DR   Bgee; ENSG00000104549; Expressed in adrenal tissue and 203 other cell types or tissues.
DR   ExpressionAtlas; Q14534; baseline and differential.
DR   GO; GO:0005783; C:endoplasmic reticulum; IBA:GO_Central.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR   GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:UniProtKB.
DR   GO; GO:0016020; C:membrane; IDA:UniProtKB.
DR   GO; GO:0071949; F:FAD binding; IDA:UniProtKB.
DR   GO; GO:0004506; F:squalene monooxygenase activity; IDA:UniProtKB.
DR   GO; GO:0008203; P:cholesterol metabolic process; IBA:GO_Central.
DR   GO; GO:0140042; P:lipid droplet formation; IMP:UniProtKB.
DR   GO; GO:0042127; P:regulation of cell population proliferation; IMP:UniProtKB.
DR   GO; GO:0010033; P:response to organic substance; IEA:Ensembl.
DR   GO; GO:0016126; P:sterol biosynthetic process; IDA:UniProtKB.
DR   Gene3D; 3.50.50.60; FAD/NAD(P)-binding domain; 1.
DR   InterPro; IPR036188; FAD/NAD-bd_sf.
DR   InterPro; IPR013698; Squalene_epoxidase.
DR   InterPro; IPR040125; Squalene_monox.
DR   PANTHER; PTHR10835; SQUALENE MONOOXYGENASE; 1.
DR   PANTHER; PTHR10835:SF0; SQUALENE MONOOXYGENASE; 1.
DR   Pfam; PF13450; NAD_binding_8; 1.
DR   Pfam; PF08491; SE; 1.
DR   PRINTS; PR00420; RNGMNOXGNASE.
DR   SUPFAM; SSF51905; FAD/NAD(P)-binding domain; 1.
DR   Genevisible; Q14534; HS.
PE   1: Evidence at protein level;
KW   3D-structure; Endoplasmic reticulum; FAD; Flavoprotein; Lipid metabolism;
KW   Membrane; Microsome; Oxidoreductase; Reference proteome; Ubl conjugation.
FT   CHAIN           1..574
FT                   /note="Squalene monooxygenase"
FT                   /id="PRO_0000209838"
FT   TOPO_DOM        1..20
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000305|PubMed:26434806"
FT   INTRAMEM        21..41
FT                   /evidence="ECO:0000305|PubMed:26434806"
FT   TOPO_DOM        42..574
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000305"
FT   REGION          1..100
FT                   /note="Interaction with MARCHF6"
FT                   /evidence="ECO:0000269|PubMed:24449766"
FT   REGION          62..73
FT                   /note="Required for degradation in response to high
FT                   membrane cholesterol levels"
FT                   /evidence="ECO:0000269|PubMed:28972164"
FT   REGION          118..574
FT                   /note="Sufficient for enzyme activity"
FT                   /evidence="ECO:0000269|PubMed:10666321,
FT                   ECO:0000269|PubMed:30626872"
FT   REGION          516..574
FT                   /note="Hydrophobic; mediates interaction with membranes"
FT                   /evidence="ECO:0000269|PubMed:30626872"
FT   BINDING         133..134
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000269|PubMed:30626872,
FT                   ECO:0007744|PDB:6C6N"
FT   BINDING         153..154
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000269|PubMed:30626872,
FT                   ECO:0007744|PDB:6C6N"
FT   BINDING         161
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000269|PubMed:30626872,
FT                   ECO:0007744|PDB:6C6N"
FT   BINDING         166
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000269|PubMed:30626872,
FT                   ECO:0007744|PDB:6C6N"
FT   BINDING         234
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000269|PubMed:30626872,
FT                   ECO:0007744|PDB:6C6N"
FT   BINDING         250
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000269|PubMed:30626872,
FT                   ECO:0007744|PDB:6C6N"
FT   BINDING         408
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000269|PubMed:30626872,
FT                   ECO:0007744|PDB:6C6N"
FT   BINDING         421
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000269|PubMed:30626872,
FT                   ECO:0007744|PDB:6C6N"
FT   SITE            195
FT                   /note="Important for enzyme activity"
FT                   /evidence="ECO:0000269|PubMed:30626872"
FT   MUTAGEN         35
FT                   /note="F->A: Increased expression levels and decreased
FT                   degradation in response to high membrane cholesterol
FT                   levels; when associated with A-37; A-65 and A-69."
FT                   /evidence="ECO:0000269|PubMed:28972164"
FT   MUTAGEN         37
FT                   /note="S->A: Increased expression levels and decreased
FT                   degradation in response to high membrane cholesterol
FT                   levels; when associated with A-35; A-65 and A-69."
FT                   /evidence="ECO:0000269|PubMed:28972164"
FT   MUTAGEN         62..73
FT                   /note="Missing: Abolishes degradation in response to high
FT                   membrane cholesterol levels."
FT                   /evidence="ECO:0000269|PubMed:28972164"
FT   MUTAGEN         65
FT                   /note="L->A: Increased expression levels and decreased
FT                   degradation in response to high membrane cholesterol
FT                   levels; when associated with A-35; A-37 and A-69."
FT                   /evidence="ECO:0000269|PubMed:28972164"
FT   MUTAGEN         69
FT                   /note="I->A: Increased expression levels and decreased
FT                   degradation in response to high membrane cholesterol
FT                   levels; when associated with A-35; A-37 and A-65."
FT                   /evidence="ECO:0000269|PubMed:28972164"
FT   MUTAGEN         195
FT                   /note="Y->A,F: Loss of enzyme activity."
FT                   /evidence="ECO:0000269|PubMed:30626872"
FT   CONFLICT        43
FT                   /note="S -> F (in Ref. 3; BX647400)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        58
FT                   /note="Q -> R (in Ref. 1; BAA22372)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        94
FT                   /note="E -> G (in Ref. 1; BAA22372)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        139
FT                   /note="A -> V (in Ref. 1; BAA22372)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        247
FT                   /note="E -> G (in Ref. 8; BAA11209)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        334
FT                   /note="I -> T (in Ref. 3; BX647400)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        336
FT                   /note="Q -> R (in Ref. 1; BAA22372)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        379..380
FT                   /note="AT -> VA (in Ref. 3; BX647400)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        389
FT                   /note="P -> L (in Ref. 1; BAA22372)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        451
FT                   /note="K -> N (in Ref. 1; BAA22372)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        518
FT                   /note="V -> A (in Ref. 1; BAA22372)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        551
FT                   /note="G -> S (in Ref. 1; BAA22372)"
FT                   /evidence="ECO:0000305"
FT   STRAND          125..129
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   HELIX           133..144
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   STRAND          149..154
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   STRAND          162..164
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   HELIX           169..177
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   HELIX           181..184
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   STRAND          190..192
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   STRAND          194..199
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   TURN            200..203
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   STRAND          204..209
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   STRAND          221..223
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   HELIX           226..238
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   STRAND          243..267
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   TURN            268..270
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   STRAND          273..277
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   STRAND          279..283
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   HELIX           286..288
FT                   /evidence="ECO:0007829|PDB:6C6R"
FT   HELIX           292..295
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   STRAND          301..313
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   STRAND          321..326
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   STRAND          328..330
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   STRAND          332..336
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   STRAND          338..348
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   HELIX           356..362
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   HELIX           365..367
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   HELIX           370..372
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   HELIX           373..382
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   STRAND          386..393
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   STRAND          403..405
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   HELIX           407..409
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   HELIX           415..417
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   HELIX           420..436
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   HELIX           444..459
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   HELIX           462..477
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   HELIX           482..496
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   HELIX           500..509
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   HELIX           516..537
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   HELIX           540..544
FT                   /evidence="ECO:0007829|PDB:6C6N"
FT   HELIX           545..566
FT                   /evidence="ECO:0007829|PDB:6C6N"
SQ   SEQUENCE   574 AA;  63923 MW;  6957F5CF1F1624C8 CRC64;
     MWTFLGIATF TYFYKKFGDF ITLANREVLL CVLVFLSLGL VLSYRCRHRN GGLLGRQQSG
     SQFALFSDIL SGLPFIGFFW AKSPPESENK EQLEARRRRK GTNISETSLI GTAACTSTSS
     QNDPEVIIVG AGVLGSALAA VLSRDGRKVT VIERDLKEPD RIVGEFLQPG GYHVLKDLGL
     GDTVEGLDAQ VVNGYMIHDQ ESKSEVQIPY PLSENNQVQS GRAFHHGRFI MSLRKAAMAE
     PNAKFIEGVV LQLLEEDDVV MGVQYKDKET GDIKELHAPL TVVADGLFSK FRKSLVSNKV
     SVSSHFVGFL MKNAPQFKAN HAELILANPS PVLIYQISSS ETRVLVDIRG EMPRNLREYM
     VEKIYPQIPD HLKEPFLEAT DNSHLRSMPA SFLPPSSVKK RGVLLLGDAY NMRHPLTGGG
     MTVAFKDIKL WRKLLKGIPD LYDDAAIFEA KKSFYWARKT SHSFVVNILA QALYELFSAT
     DDSLHQLRKA CFLYFKLGGE CVAGPVGLLS VLSPNPLVLI GHFFAVAIYA VYFCFKSEPW
     ITKPRALLSS GAVLYKACSV IFPLIYSEMK YMVH
//