ERG1_RAT
ID ERG1_RAT Reviewed; 573 AA.
AC P52020; Q4V8L3;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 1.
DT 03-AUG-2022, entry version 142.
DE RecName: Full=Squalene monooxygenase;
DE EC=1.14.14.17 {ECO:0000269|PubMed:17112472, ECO:0000269|PubMed:7814369};
DE AltName: Full=Squalene epoxidase {ECO:0000303|PubMed:7814369};
DE Short=SE {ECO:0000303|PubMed:7814369};
GN Name=Sqle; Synonyms=Erg1;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, PATHWAY, ACTIVITY
RP REGULATION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RC TISSUE=Kidney;
RX PubMed=7814369; DOI=10.1074/jbc.270.1.17;
RA Sakakibara J., Watanabe R., Kanai Y., Ono T.;
RT "Molecular cloning and expression of rat squalene epoxidase.";
RL J. Biol. Chem. 270:17-20(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
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 [3]
RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP MUTAGENESIS OF TYR-194; TYR-209; PHE-223; PHE-228; PHE-287; PHE-305;
RP TYR-334; TYR-473; PHE-476; PHE-491; PHE-522; PHE-523 AND TYR-528.
RX PubMed=17112472; DOI=10.1016/j.bbrc.2006.11.014;
RA Abe I., Abe T., Lou W., Masuoka T., Noguchi H.;
RT "Site-directed mutagenesis of conserved aromatic residues in rat squalene
RT epoxidase.";
RL Biochem. Biophys. Res. Commun. 352:259-263(2007).
CC -!- FUNCTION: Catalyzes the stereospecific oxidation of squalene to (S)-
CC 2,3-epoxysqualene, and is considered to be a rate-limiting enzyme in
CC steroid biosynthesis. {ECO:0000269|PubMed:17112472,
CC ECO:0000269|PubMed:7814369}.
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:17112472, ECO:0000269|PubMed:7814369};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000269|PubMed:17112472};
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. {ECO:0000269|PubMed:7814369}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=9.87 uM for squalene {ECO:0000269|PubMed:17112472};
CC -!- PATHWAY: Terpene metabolism; lanosterol biosynthesis; lanosterol from
CC farnesyl diphosphate: step 2/3. {ECO:0000305|PubMed:7814369}.
CC -!- SUBUNIT: Interacts (via N-terminal domain) with MARCHF6. Interacts with
CC SMIM22; this interaction modulates lipid droplet formation.
CC {ECO:0000250|UniProtKB:Q14534}.
CC -!- SUBCELLULAR LOCATION: Microsome membrane {ECO:0000269|PubMed:7814369};
CC Peripheral membrane protein {ECO:0000250|UniProtKB:Q14534}. Endoplasmic
CC reticulum membrane; Peripheral membrane protein
CC {ECO:0000250|UniProtKB:Q14534}.
CC -!- TISSUE SPECIFICITY: Detected in lever (at protein level).
CC {ECO:0000269|PubMed:7814369}.
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:0000250|UniProtKB:Q14534}.
CC -!- DOMAIN: The N-terminal region mediates interaction with MARCHF6,
CC leading to SQLE ubiquitination and proteasomal degradation when
CC cholosterol levels are high. The first part of the N-terminal region
CC contains a hydrophobic region that inserts into the membrane; contrary
CC to predictions, there are no transmembrane helices. The second part
CC contains a region that can form an amphipathic region that associates
CC with membranes. This region is ejected from the membrane by high
CC cholesterol levels and becomes disordered in an aqueous environment.
CC This is critical for cholesterol-dependent proteasomal degradation.
CC Additional parts of the N-terminal region are predicted to be
CC disordered and contribute to flagging the protein for proteasomal
CC degradation already under basal conditions.
CC {ECO:0000250|UniProtKB:Q14534}.
CC -!- PTM: Ubiquitinated by MARCHF6 in response to high cholesterol levels in
CC intracellular membranes, leading to proteasomal degradation.
CC {ECO:0000250|UniProtKB:Q14534}.
CC -!- SIMILARITY: Belongs to the squalene monooxygenase family.
CC {ECO:0000305}.
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DR EMBL; D37920; BAA07141.1; -; mRNA.
DR EMBL; BC097330; AAH97330.1; -; mRNA.
DR PIR; A55767; A55767.
DR RefSeq; NP_058832.1; NM_017136.2.
DR AlphaFoldDB; P52020; -.
DR SMR; P52020; -.
DR STRING; 10116.ENSRNOP00000012883; -.
DR BindingDB; P52020; -.
DR ChEMBL; CHEMBL4241; -.
DR DrugCentral; P52020; -.
DR jPOST; P52020; -.
DR PaxDb; P52020; -.
DR PRIDE; P52020; -.
DR Ensembl; ENSRNOT00000012883; ENSRNOP00000012883; ENSRNOG00000009550.
DR GeneID; 29230; -.
DR KEGG; rno:29230; -.
DR UCSC; RGD:3755; rat.
DR CTD; 6713; -.
DR RGD; 3755; Sqle.
DR eggNOG; KOG1298; Eukaryota.
DR GeneTree; ENSGT00390000011759; -.
DR HOGENOM; CLU_026390_0_0_1; -.
DR InParanoid; P52020; -.
DR OMA; KSKFWGL; -.
DR OrthoDB; 583514at2759; -.
DR PhylomeDB; P52020; -.
DR TreeFam; TF331056; -.
DR Reactome; R-RNO-191273; Cholesterol biosynthesis.
DR SABIO-RK; P52020; -.
DR UniPathway; UPA00767; UER00752.
DR PRO; PR:P52020; -.
DR Proteomes; UP000002494; Chromosome 7.
DR Bgee; ENSRNOG00000009550; Expressed in duodenum and 20 other tissues.
DR Genevisible; P52020; RN.
DR GO; GO:0005783; C:endoplasmic reticulum; IBA:GO_Central.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; ISS:UniProtKB.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:RGD.
DR GO; GO:0071949; F:FAD binding; ISS:UniProtKB.
DR GO; GO:0004506; F:squalene monooxygenase activity; IDA:RGD.
DR GO; GO:0006725; P:cellular aromatic compound metabolic process; IDA:RGD.
DR GO; GO:0008203; P:cholesterol metabolic process; IMP:RGD.
DR GO; GO:0140042; P:lipid droplet formation; ISS:UniProtKB.
DR GO; GO:0042127; P:regulation of cell population proliferation; ISS:UniProtKB.
DR GO; GO:0010033; P:response to organic substance; IDA:RGD.
DR GO; GO:0016126; P:sterol biosynthetic process; ISS:UniProtKB.
DR Gene3D; 3.50.50.60; -; 1.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR InterPro; IPR013698; Squalene_epoxidase.
DR InterPro; IPR040125; Squalene_monox.
DR PANTHER; PTHR10835; PTHR10835; 1.
DR Pfam; PF08491; SE; 1.
DR SUPFAM; SSF51905; SSF51905; 1.
PE 1: Evidence at protein level;
KW Endoplasmic reticulum; FAD; Flavoprotein; Lipid metabolism; Membrane;
KW Microsome; Oxidoreductase; Reference proteome; Ubl conjugation.
FT CHAIN 1..573
FT /note="Squalene monooxygenase"
FT /id="PRO_0000209840"
FT TOPO_DOM 1..19
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT INTRAMEM 20..40
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT TOPO_DOM 41..573
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT REGION 1..99
FT /note="Interaction with MARCHF6"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT REGION 61..72
FT /note="Required for degradation in response to high
FT membrane cholesterol levels"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT REGION 100..573
FT /note="Sufficient for catalytic activity"
FT /evidence="ECO:0000269|PubMed:17112472,
FT ECO:0000269|PubMed:7814369"
FT REGION 515..573
FT /note="Hydrophobic; mediates interaction with membranes"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT BINDING 132..133
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT BINDING 152..153
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT BINDING 160
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT BINDING 233
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT BINDING 249
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT BINDING 407
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT BINDING 420
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT SITE 194
FT /note="Important for enzyme activity"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT MUTAGEN 194
FT /note="Y->A: Strongly decreased catalytic activity."
FT /evidence="ECO:0000269|PubMed:17112472"
FT MUTAGEN 209
FT /note="Y->A: Nearly abolishes catalytic activity."
FT /evidence="ECO:0000269|PubMed:17112472"
FT MUTAGEN 223
FT /note="F->A: Increased enzyme activity."
FT /evidence="ECO:0000269|PubMed:17112472"
FT MUTAGEN 228
FT /note="F->A: Strongly decreased affinity for squalene."
FT /evidence="ECO:0000269|PubMed:17112472"
FT MUTAGEN 287
FT /note="F->A: Decreased enzyme activity."
FT /evidence="ECO:0000269|PubMed:17112472"
FT MUTAGEN 305
FT /note="F->A: Decreased enzyme activity."
FT /evidence="ECO:0000269|PubMed:17112472"
FT MUTAGEN 334
FT /note="Y->A: Decreased enzyme activity."
FT /evidence="ECO:0000269|PubMed:17112472"
FT MUTAGEN 473
FT /note="Y->A: Nearly abolishes enzyme activity."
FT /evidence="ECO:0000269|PubMed:17112472"
FT MUTAGEN 476
FT /note="F->A: Decreased enzyme activity."
FT /evidence="ECO:0000269|PubMed:17112472"
FT MUTAGEN 491
FT /note="F->A: Decreased enzyme activity."
FT /evidence="ECO:0000269|PubMed:17112472"
FT MUTAGEN 522
FT /note="F->A: Decreased enzyme activity."
FT /evidence="ECO:0000269|PubMed:17112472"
FT MUTAGEN 523
FT /note="F->A: Decreased enzyme activity."
FT /evidence="ECO:0000269|PubMed:17112472"
FT MUTAGEN 528
FT /note="Y->A: Decreased enzyme activity."
FT /evidence="ECO:0000269|PubMed:17112472"
SQ SEQUENCE 573 AA; 64024 MW; 55222C911E2B8777 CRC64;
MWTFLGIATF TYFYKKCGDV TLANKELLLC VLVFLSLGLV LSYRCRHRNG GLLGRHQSGS
QFAAFSDILS ALPLIGFFWA KSPPESEKKE QLESKRRRKE VNLSETTLTG AATSVSTSSV
TDPEVIIIGS GVLGSALATV LSRDGRTVTV IERDLKEPDR ILGECLQPGG YRVLRELGLG
DTVESLNAHH IHGYVIHDCE SRSEVQIPYP VSENNQVQSG VAFHHGKFIM SLRKAAMAEP
NVKFIEGVVL RLLEEDDAVI GVQYKDKETG DTKELHAPLT VVADGLFSKF RKNLISNKVS
VSSHFVGFIM KDAPQFKANF AELVLVDPSP VLIYQISPSE TRVLVDIRGE LPRNLREYMT
EQIYPQIPDH LKESFLEACQ NARLRTMPAS FLPPSSVNKR GVLLLGDAYN LRHPLTGGGM
TVALKDIKIW RQLLKDIPDL YDDAAIFQAK KSFFWSRKRS HSFVVNVLAQ ALYELFSATD
DSLRQLRKAC FLYFKLGGEC LTGPVGLLSI LSPDPLLLIR HFFSVAVYAT YFCFKSEPWA
TKPRALFSSG AILYKACSII FPLIYSEMKY LVH
