RPE65_MOUSE
ID RPE65_MOUSE Reviewed; 533 AA.
AC Q91ZQ5; A1L3D1; E9QNS6; H9KUX9; Q8VHP2;
DT 10-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT 11-DEC-2013, sequence version 4.
DT 03-AUG-2022, entry version 135.
DE RecName: Full=Retinoid isomerohydrolase;
DE EC=3.1.1.64 {ECO:0000269|PubMed:23407971};
DE AltName: Full=All-trans-retinyl-palmitate hydrolase;
DE AltName: Full=Lutein isomerase;
DE AltName: Full=Meso-zeaxanthin isomerase;
DE EC=5.3.3.22 {ECO:0000250|UniProtKB:Q16518};
DE AltName: Full=Retinal pigment epithelium-specific 65 kDa protein;
DE AltName: Full=Retinol isomerase;
GN Name=Rpe65;
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 [MRNA], FUNCTION, AND TISSUE SPECIFICITY.
RC STRAIN=C57BL/6J; TISSUE=Retina;
RX PubMed=15765048;
RA Pang J.J., Chang B., Hawes N.L., Hurd R.E., Davisson M.T., Li J.,
RA Noorwez S.M., Malhotra R., McDowell J.H., Kaushal S., Hauswirth W.W.,
RA Nusinowitz S., Thompson D.A., Heckenlively J.R.;
RT "Retinal degeneration 12 (rd12): a new, spontaneously arising mouse model
RT for human Leber congenital amaurosis (LCA).";
RL Mol. Vis. 11:152-162(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT LEU-450.
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-483.
RC STRAIN=129/Sv;
RX PubMed=11740468;
RA Boulanger A., Liu S., Yu S., Redmond T.M.;
RT "Sequence and structure of the mouse gene for RPE65.";
RL Mol. Vis. 7:283-287(2001).
RN [6]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=9843205; DOI=10.1038/3813;
RA Redmond T.M., Yu S., Lee E., Bok D., Hamasaki D., Chen N., Goletz P.,
RA Ma J.X., Crouch R.K., Pfeifer K.;
RT "Rpe65 is necessary for production of 11-cis-vitamin A in the retinal
RT visual cycle.";
RL Nat. Genet. 20:344-351(1998).
RN [7]
RP FUNCTION.
RX PubMed=17251447; DOI=10.1167/iovs.06-0652;
RA Wenzel A., von Lintig J., Oberhauser V., Tanimoto N., Grimm C.,
RA Seeliger M.W.;
RT "RPE65 is essential for the function of cone photoreceptors in NRL-
RT deficient mice.";
RL Invest. Ophthalmol. Vis. Sci. 48:534-542(2007).
RN [8]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=28500718; DOI=10.1111/php.12738;
RA Sheridan C., Boyer N.P., Crouch R.K., Koutalos Y.;
RT "RPE65 and the accumulation of retinyl esters in mouse retinal pigment
RT epithelium.";
RL Photochem. Photobiol. 93:844-848(2017).
RN [9]
RP VARIANT LEU-450.
RX PubMed=11150319; DOI=10.1523/jneurosci.21-01-00053.2001;
RA Wenzel A., Reme C.E., Williams T.P., Hafezi F., Grimm C.;
RT "The Rpe65 Leu450Met variation increases retinal resistance against light-
RT induced degeneration by slowing rhodopsin regeneration.";
RL J. Neurosci. 21:53-58(2001).
RN [10]
RP FUNCTION, CATALYTIC ACTIVITY, AND TISSUE SPECIFICITY.
RX PubMed=23407971; DOI=10.1523/jneurosci.2428-12.2013;
RA Li S., Lee J., Zhou Y., Gordon W.C., Hill J.M., Bazan N.G., Miner J.H.,
RA Jin M.;
RT "Fatty acid transport protein 4 (FATP4) prevents light-induced degeneration
RT of cone and rod photoreceptors by inhibiting RPE65 isomerase.";
RL J. Neurosci. 33:3178-3189(2013).
RN [11]
RP MUTAGENESIS OF ASP-477.
RX PubMed=29659842; DOI=10.1093/hmg/ddy128;
RA Choi E.H., Suh S., Sander C.L., Hernandez C.J.O., Bulman E.R., Khadka N.,
RA Dong Z., Shi W., Palczewski K., Kiser P.D.;
RT "Insights into the pathogenesis of dominant retinitis pigmentosa associated
RT with a D477G mutation in RPE65.";
RL Hum. Mol. Genet. 27:2225-2243(2018).
RN [12]
RP MUTAGENESIS OF ASP-477.
RX PubMed=30628748; DOI=10.1002/humu.23706;
RA Li Y., Furhang R., Ray A., Duncan T., Soucy J., Mahdi R., Chaitankar V.,
RA Gieser L., Poliakov E., Qian H., Liu P., Dong L., Rogozin I.B.,
RA Redmond T.M.;
RT "Aberrant RNA splicing is the major pathogenic effect in a knock-in mouse
RT model of the dominantly inherited c.1430A>G human RPE65 mutation.";
RL Hum. Mutat. 40:426-443(2019).
CC -!- FUNCTION: Critical isomerohydrolase in the retinoid cycle involved in
CC regeneration of 11-cis-retinal, the chromophore of rod and cone opsins.
CC Catalyzes the cleavage and isomerization of all-trans-retinyl fatty
CC acid esters to 11-cis-retinol which is further oxidized by 11-cis
CC retinol dehydrogenase to 11-cis-retinal for use as visual chromophore
CC (PubMed:15765048, PubMed:9843205, PubMed:23407971, PubMed:28500718).
CC Essential for the production of 11-cis retinal for both rod and cone
CC photoreceptors (PubMed:17251447). Also capable of catalyzing the
CC isomerization of lutein to meso-zeaxanthin an eye-specific carotenoid.
CC The soluble form binds vitamin A (all-trans-retinol), making it
CC available for LRAT processing to all-trans-retinyl ester. The membrane
CC form, palmitoylated by LRAT, binds all-trans-retinyl esters, making
CC them available for IMH (isomerohydrolase) processing to all-cis-
CC retinol. The soluble form is regenerated by transferring its palmitoyl
CC groups onto 11-cis-retinol, a reaction catalyzed by LRAT (By
CC similarity). {ECO:0000250|UniProtKB:Q16518,
CC ECO:0000250|UniProtKB:Q28175, ECO:0000269|PubMed:15765048,
CC ECO:0000269|PubMed:17251447, ECO:0000269|PubMed:23407971,
CC ECO:0000269|PubMed:28500718, ECO:0000269|PubMed:9843205}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an all-trans-retinyl ester + H2O = 11-cis-retinol + a fatty
CC acid + H(+); Xref=Rhea:RHEA:31771, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16302, ChEBI:CHEBI:28868,
CC ChEBI:CHEBI:63410; EC=3.1.1.64;
CC Evidence={ECO:0000269|PubMed:23407971};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=lutein = (3R,3'S)-zeaxanthin; Xref=Rhea:RHEA:12729,
CC ChEBI:CHEBI:28838, ChEBI:CHEBI:138919; EC=5.3.3.22;
CC Evidence={ECO:0000250|UniProtKB:Q16518};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=all-trans-retinyl hexadecanoate + H2O = 11-cis-retinol + H(+)
CC + hexadecanoate; Xref=Rhea:RHEA:31775, ChEBI:CHEBI:7896,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:16302,
CC ChEBI:CHEBI:17616; EC=3.1.1.64;
CC Evidence={ECO:0000250|UniProtKB:Q16518};
CC -!- COFACTOR:
CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033;
CC Evidence={ECO:0000250|UniProtKB:Q28175};
CC Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000250|UniProtKB:Q28175};
CC -!- SUBUNIT: Interacts with MYO7A; this mediates light-dependent
CC intracellular transport of RPE65. {ECO:0000250|UniProtKB:Q16518}.
CC -!- INTERACTION:
CC Q91ZQ5; P97479: Myo7a; NbExp=3; IntAct=EBI-11682496, EBI-1149557;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:A9C3R9}. Cell
CC membrane {ECO:0000250|UniProtKB:Q28175}; Lipid-anchor
CC {ECO:0000250|UniProtKB:Q28175}. Microsome membrane
CC {ECO:0000250|UniProtKB:Q28175}. Note=Attached to the membrane by a
CC lipid anchor when palmitoylated (membrane form), soluble when
CC unpalmitoylated. Undergoes light-dependent intracellular transport to
CC become more concentrated in the central region of the retina pigment
CC epithelium cells (By similarity). {ECO:0000250|UniProtKB:Q16518,
CC ECO:0000250|UniProtKB:Q28175}.
CC -!- TISSUE SPECIFICITY: Retinal pigment epithelium specific.
CC {ECO:0000269|PubMed:15765048, ECO:0000269|PubMed:23407971}.
CC -!- PTM: Palmitoylation by LRAT regulates ligand binding specificity; the
CC palmitoylated form (membrane form) specifically binds all-trans-
CC retinyl-palmitate, while the soluble unpalmitoylated form binds all-
CC trans-retinol (vitamin A). {ECO:0000250|UniProtKB:Q28175}.
CC -!- DISEASE: Note=Defects in Rpe65 are the cause of light damage
CC susceptibility (LDS) of the retina. {ECO:0000305|PubMed:11150319}.
CC -!- DISRUPTION PHENOTYPE: Mice exhibit changes in retinal physiology and
CC biochemistry. Outer segment disks of rod photoreceptors are
CC disorganized, rod function is abolished although cone function remains.
CC Mice lack rhodopsin, but not opsin apoprotein. Furthermore, all-trans-
CC retinyl esters over-accumulate in the retinal pigment epithelium,
CC whereas 11-cis-retinyl esters are absent. {ECO:0000269|PubMed:28500718,
CC ECO:0000269|PubMed:9843205}.
CC -!- SIMILARITY: Belongs to the carotenoid oxygenase family. {ECO:0000305}.
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DR EMBL; AF410461; AAL01119.1; -; mRNA.
DR EMBL; AC163272; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH466532; EDL11842.1; -; Genomic_DNA.
DR EMBL; BC130028; AAI30029.1; -; mRNA.
DR EMBL; AH011240; AAL39096.1; -; Genomic_DNA.
DR CCDS; CCDS38683.1; -.
DR RefSeq; NP_084263.2; NM_029987.2.
DR AlphaFoldDB; Q91ZQ5; -.
DR SMR; Q91ZQ5; -.
DR IntAct; Q91ZQ5; 1.
DR STRING; 10090.ENSMUSP00000029824; -.
DR iPTMnet; Q91ZQ5; -.
DR PhosphoSitePlus; Q91ZQ5; -.
DR PaxDb; Q91ZQ5; -.
DR PRIDE; Q91ZQ5; -.
DR ProteomicsDB; 299871; -.
DR Antibodypedia; 33418; 249 antibodies from 33 providers.
DR DNASU; 19892; -.
DR Ensembl; ENSMUST00000029824; ENSMUSP00000029824; ENSMUSG00000028174.
DR Ensembl; ENSMUST00000196999; ENSMUSP00000143654; ENSMUSG00000028174.
DR GeneID; 19892; -.
DR KEGG; mmu:19892; -.
DR UCSC; uc008rwb.1; mouse.
DR CTD; 6121; -.
DR MGI; MGI:98001; Rpe65.
DR VEuPathDB; HostDB:ENSMUSG00000028174; -.
DR eggNOG; KOG1285; Eukaryota.
DR GeneTree; ENSGT00950000182913; -.
DR InParanoid; Q91ZQ5; -.
DR OMA; HHIPYGL; -.
DR OrthoDB; 895046at2759; -.
DR PhylomeDB; Q91ZQ5; -.
DR TreeFam; TF314019; -.
DR BRENDA; 3.1.1.64; 3474.
DR Reactome; R-MMU-2453902; The canonical retinoid cycle in rods (twilight vision).
DR BioGRID-ORCS; 19892; 1 hit in 71 CRISPR screens.
DR PRO; PR:Q91ZQ5; -.
DR Proteomes; UP000000589; Chromosome 3.
DR RNAct; Q91ZQ5; protein.
DR Bgee; ENSMUSG00000028174; Expressed in pigmented layer of retina and 10 other tissues.
DR ExpressionAtlas; Q91ZQ5; baseline and differential.
DR Genevisible; Q91ZQ5; MM.
DR GO; GO:0044297; C:cell body; ISO:MGI.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; ISS:UniProtKB.
DR GO; GO:0016020; C:membrane; ISS:AgBase.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0052885; F:all-trans-retinyl-ester hydrolase, 11-cis retinol forming activity; ISS:AgBase.
DR GO; GO:0052884; F:all-trans-retinyl-palmitate hydrolase, 11-cis retinol forming activity; ISS:UniProtKB.
DR GO; GO:1901612; F:cardiolipin binding; ISS:AgBase.
DR GO; GO:0016853; F:isomerase activity; ISS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0016702; F:oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen; IEA:InterPro.
DR GO; GO:0031210; F:phosphatidylcholine binding; ISS:AgBase.
DR GO; GO:0001786; F:phosphatidylserine binding; ISS:AgBase.
DR GO; GO:0004744; F:retinal isomerase activity; IMP:MGI.
DR GO; GO:0050251; F:retinol isomerase activity; IBA:GO_Central.
DR GO; GO:0071257; P:cellular response to electrical stimulus; IMP:MGI.
DR GO; GO:0007623; P:circadian rhythm; IEA:Ensembl.
DR GO; GO:0050908; P:detection of light stimulus involved in visual perception; ISO:MGI.
DR GO; GO:0008286; P:insulin receptor signaling pathway; IMP:MGI.
DR GO; GO:0003407; P:neural retina development; ISO:MGI.
DR GO; GO:0010468; P:regulation of gene expression; IMP:MGI.
DR GO; GO:0060041; P:retina development in camera-type eye; IMP:MGI.
DR GO; GO:0001895; P:retina homeostasis; ISO:MGI.
DR GO; GO:0060042; P:retina morphogenesis in camera-type eye; IMP:MGI.
DR GO; GO:0042574; P:retinal metabolic process; IMP:MGI.
DR GO; GO:0001523; P:retinoid metabolic process; ISS:UniProtKB.
DR GO; GO:0042572; P:retinol metabolic process; ISO:MGI.
DR GO; GO:0007601; P:visual perception; IMP:MGI.
DR GO; GO:1901827; P:zeaxanthin biosynthetic process; ISS:UniProtKB.
DR InterPro; IPR004294; Carotenoid_Oase.
DR PANTHER; PTHR10543; PTHR10543; 1.
DR Pfam; PF03055; RPE65; 1.
PE 1: Evidence at protein level;
KW Acetylation; Cell membrane; Cytoplasm; Disease variant;
KW Endoplasmic reticulum; Hydrolase; Iron; Isomerase; Lipid metabolism;
KW Lipoprotein; Membrane; Metal-binding; Microsome; Palmitate; Phosphoprotein;
KW Reference proteome; Sensory transduction; Vision.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:Q28175"
FT CHAIN 2..533
FT /note="Retinoid isomerohydrolase"
FT /id="PRO_0000143944"
FT BINDING 180
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q28175"
FT BINDING 241
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q28175"
FT BINDING 313
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q28175"
FT BINDING 527
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q28175"
FT MOD_RES 2
FT /note="N-acetylserine"
FT /evidence="ECO:0000250|UniProtKB:Q28175"
FT MOD_RES 101
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q16518"
FT MOD_RES 105
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q16518"
FT MOD_RES 113
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q16518"
FT MOD_RES 117
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q16518"
FT LIPID 112
FT /note="S-palmitoyl cysteine; in membrane form"
FT /evidence="ECO:0000250|UniProtKB:Q28175"
FT LIPID 231
FT /note="S-palmitoyl cysteine; in membrane form"
FT /evidence="ECO:0000250|UniProtKB:Q28175"
FT LIPID 329
FT /note="S-palmitoyl cysteine; in membrane form"
FT /evidence="ECO:0000250|UniProtKB:Q28175"
FT LIPID 330
FT /note="S-palmitoyl cysteine; in membrane form"
FT /evidence="ECO:0000250|UniProtKB:Q28175"
FT VARIANT 450
FT /note="M -> L (increased light damage susceptibility)"
FT /evidence="ECO:0000269|PubMed:11150319,
FT ECO:0000269|PubMed:19468303"
FT MUTAGEN 477
FT /note="D->G: Knockin mice exhibit mild age-dependent
FT degeneration of retinal structure and function; Knockin
FT mice exhibit adequate isomerization activity with an
FT accumulation of retinyl esters and a delay in rhodopsin
FT regeneration kinetics and diminished electroretinography
FT responses. Retinae of knockin mice are more sensitive to
FT light exposition and exhibit signs of degenerative features
FT when sujected to light stress. May cause abnormal splicing
FT mRNAs thereby decreasing protein levels."
FT /evidence="ECO:0000269|PubMed:29659842,
FT ECO:0000269|PubMed:30628748"
SQ SEQUENCE 533 AA; 61085 MW; BBDA3EBDF5B7A5E2 CRC64;
MSIQIEHPAG GYKKLFETVE ELSSPLTAHV TGRIPLWLTG SLLRCGPGLF EVGSEPFYHL
FDGQALLHKF DFKEGHVTYH RRFIRTDAYV RAMTEKRIVI TEFGTCAFPD PCKNIFSRFF
SYFKGVEVTD NALVNIYPVG EDYYACTETN FITKINPETL ETIKQVDLCN YISVNGATAH
PHIESDGTVY NIGNCFGKNF TVAYNIIKIP PLKADKEDPI NKSEVVVQFP CSDRFKPSYV
HSFGLTPNYI VFVETPVKIN LFKFLSSWSL WGANYMDCFE SNESMGVWLH VADKKRRKYF
NNKYRTSPFN LFHHINTYED NGFLIVDLCC WKGFEFVYNY LYLANLRENW EEVKRNAMKA
PQPEVRRYVL PLTIDKVDTG RNLVTLPHTT ATATLRSDET IWLEPEVLFS GPRQAFEFPQ
INYQKFGGKP YTYAYGLGLN HFVPDKLCKM NVKTKEIWMW QEPDSYPSEP IFVSQPDALE
EDDGVVLSVV VSPGAGQKPA YLLVLNAKDL SEIARAEVET NIPVTFHGLF KRS
