ID ORML3_MOUSE Reviewed; 153 AA.
AC Q9CPZ6; A2A4X7; Q8BN65; Q8R0U5;
DT 08-NOV-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2001, sequence version 1.
DT 02-SEP-2026, entry version 146.
DE RecName: Full=ORM1-like protein 3;
GN Name=Ormdl3;
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].
RC STRAIN=C57BL/6J, and NOD; TISSUE=Eye, Thymus, and Tongue;
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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon, and Olfactory epithelium;
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 [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=31880535; DOI=10.7554/elife.51067;
RA Clarke B.A., Majumder S., Zhu H., Lee Y.T., Kono M., Li C., Khanna C.,
RA Blain H., Schwartz R., Huso V.L., Byrnes C., Tuymetova G., Dunn T.M.,
RA Allende M.L., Proia R.L.;
RT "The Ormdl genes regulate the sphingolipid synthesis pathway to ensure
RT proper myelination and neurologic function in mice.";
RL Elife 8:0-0(2019).
RN [6]
RP FUNCTION.
RX PubMed=30700557; DOI=10.1074/jbc.ra118.007291;
RA Davis D.L., Gable K., Suemitsu J., Dunn T.M., Wattenberg B.W.;
RT "The ORMDL/Orm-serine palmitoyltransferase (SPT) complex is directly
RT regulated by ceramide: Reconstitution of SPT regulation in isolated
RT membranes.";
RL J. Biol. Chem. 294:5146-5156(2019).
CC -!- FUNCTION: Plays an essential role in the homeostatic regulation of
CC sphingolipid de novo biosynthesis by modulating the activity of the
CC serine palmitoyltransferase (SPT) in response to ceramide levels
CC (PubMed:30700557, PubMed:31880535). When complexed to SPT, the binding
CC of ceramides to its N-terminus stabilizes a conformation that block SPT
CC substrate entry, hence preventing SPT catalytic activity. Through this
CC mechanism, maintains ceramide levels at sufficient concentrations for
CC the production of complex sphingolipids, but which prevents the
CC accumulation of ceramides to levels that trigger apoptosis (By
CC similarity). {ECO:0000250|UniProtKB:Q8N138,
CC ECO:0000269|PubMed:30700557, ECO:0000269|PubMed:31880535}.
CC -!- SUBUNIT: Ceramide-sensitive subunit of the serine palmitoyltransferase
CC (SPT) complex, which is also composed of SPTLC1, SPTLC2/3 and SPTSSA/B.
CC {ECO:0000250|UniProtKB:Q8N138}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:Q8N138}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q8N138}.
CC -!- DOMAIN: Ceramides bind to ORMDL3 N-terminus and stabilize it in a
CC conformation that physically restricts the accessibility of the
CC substrates to their binding sites in the serine palmitoyltransferase
CC (SPT) complex, hence inhibiting SPT catalytic activity. In the absence
CC of ceramides, the N-terminus is flexible and permits substrate binding,
CC thus liberating SPT from inhibition. {ECO:0000250|UniProtKB:Q8N138}.
CC -!- PTM: When hydroxylated at Pro-137, ubiquitinated via 'Lys-48'-linkage,
CC leading to proteasomal degradation. In endothelial cells, ORMDL3
CC proteasomal degradation is controlled by the sphingosine 1-phosphate
CC receptor signaling pathway. {ECO:0000250|UniProtKB:Q8N138}.
CC -!- DISRUPTION PHENOTYPE: No overt phenotype, although knockout mice show
CC elevated brain levels of sphingolipids, including dihydrosphingosine,
CC dihydroceramide, ceramide and sphingosine, compared with wild-type
CC animals (PubMed:31880535). Double knockdown of ORMDL1 and ORMDL3 show
CC elevated brain levels of sphingolipids, compared with single knockout
CC and wild-type animals (PubMed:31880535). At 8 weeks of age, both male
CC and female ORMDL1/3 double knockout mice weigh significantly less than
CC wild-type mice and exhibit impaired myelination and motor-function
CC abnormalities (PubMed:31880535). The triple knockout ORMDL1, ORMDL2 and
CC ORMDL3 is not viable (PubMed:31880535). {ECO:0000269|PubMed:31880535}.
CC -!- SIMILARITY: Belongs to the ORM family. {ECO:0000305}.
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DR EMBL; AK009621; BAB26397.1; -; mRNA.
DR EMBL; AK012718; BAB28432.1; -; mRNA.
DR EMBL; AK154085; BAE32363.1; -; mRNA.
DR EMBL; AK087497; BAC39898.1; -; mRNA.
DR EMBL; AL591125; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH466556; EDL16151.1; -; Genomic_DNA.
DR EMBL; BC026412; AAH26412.1; -; mRNA.
DR EMBL; BC046594; AAH46594.1; -; mRNA.
DR CCDS; CCDS25355.1; -.
DR RefSeq; NP_079937.1; NM_025661.4.
DR AlphaFoldDB; Q9CPZ6; -.
DR SMR; Q9CPZ6; -.
DR BioGRID; 211595; 3.
DR FunCoup; Q9CPZ6; 1170.
DR IntAct; Q9CPZ6; 1.
DR STRING; 10090.ENSMUSP00000053056; -.
DR iPTMnet; Q9CPZ6; -.
DR PhosphoSitePlus; Q9CPZ6; -.
DR jPOST; Q9CPZ6; -.
DR PaxDb; 10090-ENSMUSP00000053056; -.
DR PeptideAtlas; Q9CPZ6; -.
DR ProteomicsDB; 295475; -.
DR Pumba; Q9CPZ6; -.
DR TopDownProteomics; Q9CPZ6; -.
DR Antibodypedia; 54876; 115 antibodies from 24 providers.
DR DNASU; 66612; -.
DR Ensembl; ENSMUST00000052919.8; ENSMUSP00000053056.8; ENSMUSG00000038150.8.
DR GeneID; 66612; -.
DR KEGG; mmu:66612; -.
DR UCSC; uc007lgr.1; mouse.
DR AGR; MGI:1913862; -.
DR CTD; 94103; -.
DR MGI; MGI:1913862; Ormdl3.
DR VEuPathDB; HostDB:ENSMUSG00000038150; -.
DR eggNOG; KOG3319; Eukaryota.
DR GeneTree; ENSGT00950000183178; -.
DR HOGENOM; CLU_072117_3_0_1; -.
DR InParanoid; Q9CPZ6; -.
DR OMA; WTAYILI; -.
DR OrthoDB; 1932233at2759; -.
DR PhylomeDB; Q9CPZ6; -.
DR Reactome; R-MMU-1660661; Sphingolipid de novo biosynthesis.
DR Reactome; R-MMU-6798695; Neutrophil degranulation.
DR BioGRID-ORCS; 66612; 7 hits in 78 CRISPR screens.
DR PRO; PR:Q9CPZ6; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; Q9CPZ6; protein.
DR Bgee; ENSMUSG00000038150; Expressed in olfactory epithelium and 253 other cell types or tissues.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; ISS:UniProtKB.
DR GO; GO:0017059; C:serine palmitoyltransferase complex; ISS:UniProtKB.
DR GO; GO:0006672; P:ceramide metabolic process; ISS:UniProtKB.
DR GO; GO:0002903; P:negative regulation of B cell apoptotic process; IMP:MGI.
DR GO; GO:1900060; P:negative regulation of ceramide biosynthetic process; IDA:MGI.
DR GO; GO:0010508; P:positive regulation of autophagy; IMP:MGI.
DR GO; GO:1900182; P:positive regulation of protein localization to nucleus; ISO:MGI.
DR InterPro; IPR007203; ORMDL.
DR PANTHER; PTHR12665; ORMDL PROTEINS; 1.
DR Pfam; PF04061; ORMDL; 1.
DR PIRSF; PIRSF018147; ORMDL; 1.
PE 2: Evidence at transcript level;
KW Endoplasmic reticulum; Hydroxylation; Membrane; Reference proteome;
KW Transmembrane; Transmembrane helix; Ubl conjugation.
FT CHAIN 1..153
FT /note="ORM1-like protein 3"
FT /id="PRO_0000215640"
FT TOPO_DOM 1..21
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q8N138, ECO:0000255"
FT TRANSMEM 22..42
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q8N138, ECO:0000255"
FT TRANSMEM 43..63
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q8N138, ECO:0000255"
FT TOPO_DOM 64..94
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q8N138, ECO:0000255"
FT TRANSMEM 95..117
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q8N138, ECO:0000255"
FT TOPO_DOM 118..121
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q8N138, ECO:0000255"
FT TRANSMEM 122..142
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q8N138, ECO:0000255"
FT TOPO_DOM 143..153
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q8N138, ECO:0000255"
FT REGION 1..17
FT /note="Important for ceramide level-sensing"
FT /evidence="ECO:0000250|UniProtKB:Q8N138"
FT MOD_RES 137
FT /note="Hydroxyproline"
FT /evidence="ECO:0000250|UniProtKB:Q8N138"
FT CONFLICT 58
FT /note="L -> Q (in Ref. 1; BAC39898)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 153 AA; 17477 MW; E37EB8D0E958EB2D CRC64;
MNVGTAHSEV NPNTRVMNSR GIWLSYVLAI GLLHVVLLSI PFVSVPVVWT LTNLIHNLGM
YIFLHTVKGT PFETPDQGKA RLLTHWEQMD YGVQFTASRK FLTITPIVLY FLTSFYTKYD
QVHFILNTVS LMTVLIPKLP QLHGVRIFGI NKY
//
