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 27-MAR-2024, entry version 144. 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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.ENSMUSP00000143654; -. DR iPTMnet; Q91ZQ5; -. DR PhosphoSitePlus; Q91ZQ5; -. DR PaxDb; 10090-ENSMUSP00000029824; -. DR ProteomicsDB; 299871; -. DR Antibodypedia; 33418; 289 antibodies from 33 providers. DR DNASU; 19892; -. DR Ensembl; ENSMUST00000029824.9; ENSMUSP00000029824.9; ENSMUSG00000028174.13. DR Ensembl; ENSMUST00000196999.5; ENSMUSP00000143654.2; ENSMUSG00000028174.13. DR GeneID; 19892; -. DR KEGG; mmu:19892; -. DR UCSC; uc008rwb.1; mouse. DR AGR; MGI:98001; -. DR CTD; 6121; -. DR MGI; MGI:98001; Rpe65. DR VEuPathDB; HostDB:ENSMUSG00000028174; -. DR eggNOG; KOG1285; Eukaryota. DR GeneTree; ENSGT00950000182913; -. DR InParanoid; Q91ZQ5; -. DR OMA; VHHPFDG; -. DR OrthoDB; 294919at2759; -. 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 76 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 12 other cell types or tissues. DR ExpressionAtlas; Q91ZQ5; baseline and differential. 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:0003834; F:beta-carotene 15,15'-dioxygenase activity; IBA:GO_Central. 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:0031210; F:phosphatidylcholine binding; ISS:AgBase. DR GO; GO:0001786; F:phosphatidylserine binding; ISS:AgBase. DR GO; GO:0050251; F:retinol isomerase activity; IBA:GO_Central. 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:0003407; P:neural retina development; ISO:MGI. DR GO; GO:0001895; P:retina homeostasis; ISO:MGI. DR GO; GO:0042574; P:retinal metabolic process; ISO:MGI. DR GO; GO:0001523; P:retinoid metabolic process; ISS:UniProtKB. DR GO; GO:0042572; P:retinol metabolic process; ISO:MGI. DR GO; GO:1901827; P:zeaxanthin biosynthetic process; ISS:UniProtKB. DR InterPro; IPR004294; Carotenoid_Oase. DR PANTHER; PTHR10543; BETA-CAROTENE DIOXYGENASE; 1. DR PANTHER; PTHR10543:SF57; RETINOID ISOMEROHYDROLASE; 1. DR Pfam; PF03055; RPE65; 1. DR Genevisible; Q91ZQ5; MM. 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 //