AT8A2_MOUSE
ID AT8A2_MOUSE Reviewed; 1148 AA.
AC P98200; B2RQF2;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 30-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 172.
DE RecName: Full=Phospholipid-transporting ATPase IB {ECO:0000305};
DE EC=7.6.2.1 {ECO:0000250|UniProtKB:C7EXK4};
DE AltName: Full=ATPase class I type 8A member 2;
DE AltName: Full=P4-ATPase flippase complex alpha subunit ATP8A2;
GN Name=Atp8a2 {ECO:0000312|MGI:MGI:1354710};
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].
RC STRAIN=ICR;
RX PubMed=11015572; DOI=10.1152/physiolgenomics.1999.1.3.139;
RA Halleck M.S., Lawler J.F. Jr., Blackshaw S., Gao L., Nagarajan P.,
RA Hacker C., Pyle S., Newman J.T., Nakanishi Y., Ando H., Weinstock D.,
RA Williamson P.L., Schlegel R.A.;
RT "Differential expression of putative transbilayer amphipath transporters.";
RL Physiol. Genomics 1:139-150(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 TISSUE SPECIFICITY.
RX PubMed=19778899; DOI=10.1074/jbc.m109.047415;
RA Coleman J.A., Kwok M.C., Molday R.S.;
RT "Localization, purification, and functional reconstitution of the P4-ATPase
RT Atp8a2, a phosphatidylserine flippase in photoreceptor disc membranes.";
RL J. Biol. Chem. 284:32670-32679(2009).
RN [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-5, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [5]
RP FUNCTION, AND MUTAGENESIS OF ASP-388.
RX PubMed=22641037; DOI=10.1016/j.febslet.2012.05.018;
RA Xu Q., Yang G.Y., Liu N., Xu P., Chen Y.L., Zhou Z., Luo Z.G., Ding X.;
RT "P4-ATPase ATP8A2 acts in synergy with CDC50A to enhance neurite
RT outgrowth.";
RL FEBS Lett. 586:1803-1812(2012).
RN [6]
RP FUNCTION, TISSUE SPECIFICITY, DISRUPTION PHENOTYPE, INVOLVEMENT IN WL,
RP VARIANT WL 637-THR--LEU-643 DEL, AND MUTAGENESIS OF ASP-388.
RX PubMed=22912588; DOI=10.1371/journal.pgen.1002853;
RA Zhu X., Libby R.T., de Vries W.N., Smith R.S., Wright D.L., Bronson R.T.,
RA Seburn K.L., John S.W.;
RT "Mutations in a P-type ATPase gene cause axonal degeneration.";
RL PLoS Genet. 8:E1002853-E1002853(2012).
RN [7]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=24413176; DOI=10.1242/jcs.145052;
RA Coleman J.A., Zhu X., Djajadi H.R., Molday L.L., Smith R.S., Libby R.T.,
RA John S.W., Molday R.S.;
RT "Phospholipid flippase ATP8A2 is required for normal visual and auditory
RT function and photoreceptor and spiral ganglion cell survival.";
RL J. Cell Sci. 127:1138-1149(2014).
CC -!- FUNCTION: Catalytic component of a P4-ATPase flippase complex which
CC catalyzes the hydrolysis of ATP coupled to the transport of
CC aminophospholipids from the outer to the inner leaflet of various
CC membranes and ensures the maintenance of asymmetric distribution of
CC phospholipids (PubMed:22912588). Phospholipid translocation seems also
CC to be implicated in vesicle formation and in uptake of lipid signaling
CC molecules. Reconstituted to liposomes, the ATP8A2:TMEM30A flippase
CC complex predominantly transports phosphatidylserine (PS) and to a
CC lesser extent phosphatidylethanolamine (PE) (PubMed:22912588).
CC Phospholipid translocation is not associated with a countertransport of
CC an inorganic ion or other charged substrate from the cytoplasmic side
CC toward the exoplasm in connection with the phosphorylation from ATP (By
CC similarity). ATP8A2:TMEM30A may be involved in regulation of neurite
CC outgrowth (PubMed:22641037). Proposed to function in the generation and
CC maintenance of phospholipid asymmetry in photoreceptor disk membranes
CC and neuronal axon membranes. May be involved in vesicle trafficking in
CC neuronal cells. Required for normal visual and auditory function;
CC involved in photoreceptor and inner ear spiral ganglion cell survival
CC (PubMed:24413176). {ECO:0000250|UniProtKB:C7EXK4,
CC ECO:0000269|PubMed:22641037, ECO:0000269|PubMed:22912588,
CC ECO:0000269|PubMed:24413176}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + H2O + phospholipidSide 1 = ADP + phosphate +
CC phospholipidSide 2.; EC=7.6.2.1;
CC Evidence={ECO:0000250|UniProtKB:C7EXK4};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-L-serine(out) + ATP + H2O =
CC a 1,2-diacyl-sn-glycero-3-phospho-L-serine(in) + ADP + H(+) +
CC phosphate; Xref=Rhea:RHEA:38567, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:57262, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000250|UniProtKB:C7EXK4};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38568;
CC Evidence={ECO:0000250|UniProtKB:C7EXK4};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phosphoethanolamine(in) + ATP + H2O
CC = a 1,2-diacyl-sn-glycero-3-phosphoethanolamine(out) + ADP + H(+) +
CC phosphate; Xref=Rhea:RHEA:36439, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:64612, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000250|UniProtKB:C7EXK4};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:36440;
CC Evidence={ECO:0000250|UniProtKB:C7EXK4};
CC -!- SUBUNIT: Component of a P4-ATPase flippase complex which consists of a
CC catalytic alpha subunit and an accessory beta subunit. Interacts with
CC TMEM30A to form a flippase complex. {ECO:0000250|UniProtKB:C7EXK4}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000305|PubMed:24413176}; Multi-
CC pass membrane protein {ECO:0000255}. Golgi apparatus membrane
CC {ECO:0000269|PubMed:24413176}. Endosome membrane
CC {ECO:0000269|PubMed:24413176}. Cell membrane
CC {ECO:0000269|PubMed:24413176}. Photoreceptor outer segment membrane
CC {ECO:0000269|PubMed:24413176}. Photoreceptor inner segment membrane
CC {ECO:0000250|UniProtKB:C7EXK4}. Note=Localizes to the Golgi and
CC endosomes in photoreceptor cells (PubMed:24413176). Localizes to disk
CC membranes of rod photoreceptor outer segments (ROS) (By similarity).
CC {ECO:0000250|UniProtKB:C7EXK4, ECO:0000269|PubMed:24413176}.
CC -!- TISSUE SPECIFICITY: Found in testis, heart and brain. Most abundant in
CC testis. Also detected in fetal tissues. Expressed in retinal
CC photoreceptor cells; detected in retina outer nuclear layer and inner
CC segment (at protein level). {ECO:0000269|PubMed:19778899,
CC ECO:0000269|PubMed:22912588}.
CC -!- DISEASE: Note=Defects in Atp8a2 are the cause of Wabbler-lethal (wl)
CC phenotype. Homozygotes show severe neurological annormalities that
CC include ataxia and body tremors linked to progressive axonal
CC degeneration in several areas of the nervous system.
CC {ECO:0000269|PubMed:22912588}.
CC -!- DISRUPTION PHENOTYPE: Atp8a2 and Atp8a1 double mutant mice die soon
CC after birth. {ECO:0000269|PubMed:22912588}.
CC -!- SIMILARITY: Belongs to the cation transport ATPase (P-type) (TC 3.A.3)
CC family. Type IV subfamily. {ECO:0000305}.
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DR EMBL; AF156550; AAF09448.1; -; mRNA.
DR EMBL; BC137896; AAI37897.1; -; mRNA.
DR CCDS; CCDS27174.1; -.
DR RefSeq; NP_056618.1; NM_015803.2.
DR RefSeq; XP_006519297.1; XM_006519234.3.
DR RefSeq; XP_006519298.1; XM_006519235.3.
DR AlphaFoldDB; P98200; -.
DR SMR; P98200; -.
DR BioGRID; 206101; 1.
DR STRING; 10090.ENSMUSP00000079238; -.
DR TCDB; 3.A.3.8.8; the p-type atpase (p-atpase) superfamily.
DR iPTMnet; P98200; -.
DR jPOST; P98200; -.
DR MaxQB; P98200; -.
DR PaxDb; P98200; -.
DR PeptideAtlas; P98200; -.
DR PRIDE; P98200; -.
DR ProteomicsDB; 277086; -.
DR Antibodypedia; 50027; 97 antibodies from 16 providers.
DR DNASU; 50769; -.
DR Ensembl; ENSMUST00000080368; ENSMUSP00000079238; ENSMUSG00000021983.
DR GeneID; 50769; -.
DR KEGG; mmu:50769; -.
DR UCSC; uc007uet.1; mouse.
DR CTD; 51761; -.
DR MGI; MGI:1354710; Atp8a2.
DR VEuPathDB; HostDB:ENSMUSG00000021983; -.
DR eggNOG; KOG0206; Eukaryota.
DR GeneTree; ENSGT00940000157332; -.
DR HOGENOM; CLU_000846_3_0_1; -.
DR InParanoid; P98200; -.
DR OMA; YWEIGVQ; -.
DR OrthoDB; 587717at2759; -.
DR PhylomeDB; P98200; -.
DR TreeFam; TF300654; -.
DR BRENDA; 7.6.2.1; 3474.
DR Reactome; R-MMU-936837; Ion transport by P-type ATPases.
DR BioGRID-ORCS; 50769; 3 hits in 77 CRISPR screens.
DR ChiTaRS; Atp8a2; mouse.
DR PRO; PR:P98200; -.
DR Proteomes; UP000000589; Chromosome 14.
DR RNAct; P98200; protein.
DR Bgee; ENSMUSG00000021983; Expressed in lumbar dorsal root ganglion and 166 other tissues.
DR ExpressionAtlas; P98200; baseline and differential.
DR Genevisible; P98200; MM.
DR GO; GO:0042995; C:cell projection; IEA:UniProtKB-KW.
DR GO; GO:0005768; C:endosome; IDA:UniProtKB.
DR GO; GO:0010008; C:endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016020; C:membrane; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:1990531; C:phospholipid-translocating ATPase complex; ISO:MGI.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0015247; F:aminophospholipid flippase activity; IMP:GO_Central.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0016887; F:ATP hydrolysis activity; IEA:InterPro.
DR GO; GO:0140326; F:ATPase-coupled intramembrane lipid transporter activity; IBA:GO_Central.
DR GO; GO:0000287; F:magnesium ion binding; IEA:InterPro.
DR GO; GO:0090555; F:phosphatidylethanolamine flippase activity; ISS:UniProtKB.
DR GO; GO:0140346; F:phosphatidylserine flippase activity; ISS:UniProtKB.
DR GO; GO:0090556; F:phosphatidylserine floppase activity; IEA:RHEA.
DR GO; GO:0007568; P:aging; IMP:MGI.
DR GO; GO:0140331; P:aminophospholipid translocation; ISS:UniProtKB.
DR GO; GO:0007409; P:axonogenesis; IMP:MGI.
DR GO; GO:0050908; P:detection of light stimulus involved in visual perception; IMP:UniProtKB.
DR GO; GO:0042755; P:eating behavior; IMP:MGI.
DR GO; GO:0042472; P:inner ear morphogenesis; IMP:UniProtKB.
DR GO; GO:0003011; P:involuntary skeletal muscle contraction; IMP:MGI.
DR GO; GO:0060052; P:neurofilament cytoskeleton organization; IMP:UniProtKB.
DR GO; GO:0050884; P:neuromuscular process controlling posture; IMP:MGI.
DR GO; GO:0048666; P:neuron development; IMP:MGI.
DR GO; GO:0031175; P:neuron projection development; ISO:MGI.
DR GO; GO:0045332; P:phospholipid translocation; IBA:GO_Central.
DR GO; GO:0040018; P:positive regulation of multicellular organism growth; IMP:MGI.
DR GO; GO:0010976; P:positive regulation of neuron projection development; IDA:UniProtKB.
DR GO; GO:0061092; P:positive regulation of phospholipid translocation; IDA:UniProtKB.
DR GO; GO:0010996; P:response to auditory stimulus; IMP:UniProtKB.
DR GO; GO:0010842; P:retina layer formation; IMP:UniProtKB.
DR GO; GO:0043588; P:skin development; IMP:MGI.
DR Gene3D; 3.40.1110.10; -; 1.
DR Gene3D; 3.40.50.1000; -; 1.
DR InterPro; IPR023299; ATPase_P-typ_cyto_dom_N.
DR InterPro; IPR018303; ATPase_P-typ_P_site.
DR InterPro; IPR023298; ATPase_P-typ_TM_dom_sf.
DR InterPro; IPR008250; ATPase_P-typ_transduc_dom_A_sf.
DR InterPro; IPR036412; HAD-like_sf.
DR InterPro; IPR023214; HAD_sf.
DR InterPro; IPR006539; P-type_ATPase_IV.
DR InterPro; IPR032631; P-type_ATPase_N.
DR InterPro; IPR001757; P_typ_ATPase.
DR InterPro; IPR032630; P_typ_ATPase_c.
DR InterPro; IPR044492; P_typ_ATPase_HD_dom.
DR Pfam; PF16212; PhoLip_ATPase_C; 1.
DR Pfam; PF16209; PhoLip_ATPase_N; 1.
DR SFLD; SFLDF00027; p-type_atpase; 1.
DR SUPFAM; SSF56784; SSF56784; 1.
DR SUPFAM; SSF81653; SSF81653; 1.
DR SUPFAM; SSF81660; SSF81660; 1.
DR SUPFAM; SSF81665; SSF81665; 1.
DR TIGRFAMs; TIGR01652; ATPase-Plipid; 1.
DR TIGRFAMs; TIGR01494; ATPase_P-type; 2.
DR PROSITE; PS00154; ATPASE_E1_E2; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Cell membrane; Cell projection; Disease variant; Endosome;
KW Golgi apparatus; Lipid transport; Magnesium; Membrane; Metal-binding;
KW Nucleotide-binding; Phosphoprotein; Reference proteome; Translocase;
KW Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..1148
FT /note="Phospholipid-transporting ATPase IB"
FT /id="PRO_0000046363"
FT TOPO_DOM 1..44
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 45..66
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 67..71
FT /note="Exoplasmic loop"
FT /evidence="ECO:0000255"
FT TRANSMEM 72..94
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 95..276
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 277..298
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 299..323
FT /note="Exoplasmic loop"
FT /evidence="ECO:0000255"
FT TRANSMEM 324..345
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 346..837
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 838..858
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 859..870
FT /note="Exoplasmic loop"
FT /evidence="ECO:0000255"
FT TRANSMEM 871..890
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 891..920
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 921..942
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 943..956
FT /note="Exoplasmic loop"
FT /evidence="ECO:0000255"
FT TRANSMEM 957..979
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 980..985
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 986..1006
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1007..1024
FT /note="Exoplasmic loop"
FT /evidence="ECO:0000255"
FT TRANSMEM 1025..1049
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1050..1148
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT ACT_SITE 388
FT /note="4-aspartylphosphate intermediate"
FT /evidence="ECO:0000250"
FT BINDING 781
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250"
FT BINDING 785
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250"
FT SITE 331
FT /note="Involved in the recognition of the lipid substrate
FT on the exoplasmic side"
FT /evidence="ECO:0000250|UniProtKB:C7EXK4"
FT SITE 336
FT /note="Involved in the release of the transported lipid
FT into the cytosolic leaflet"
FT /evidence="ECO:0000250|UniProtKB:C7EXK4"
FT MOD_RES 5
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT VARIANT 637..643
FT /note="Missing (in wl; abolishes phosphatidylserine
FT translocase activity)"
FT /evidence="ECO:0000269|PubMed:22912588"
FT MUTAGEN 388
FT /note="D->A: Abolishes phosphatidylserine translocase
FT activity, abolishes effect on neurite outgrowth."
FT /evidence="ECO:0000269|PubMed:22641037,
FT ECO:0000269|PubMed:22912588"
SQ SEQUENCE 1148 AA; 129417 MW; A668D6F343CAAAB8 CRC64;
MSRATSVGDQ LEAPARIIYL NQSHLNKFCD NRISTAKYSV LTFLPRFLYE QIRRAANAFF
LFIALLQQIP DVSPTGRYTT LVPLVIILTI AGIKEIIEDF KRHKADNAVN KKKTIVLRNG
MWHTIMWKEV AVGDIVKVLN GQYLPADMVL FSSSEPQGMC YVETANLDGE TNLKIRQGLS
HTTDMQTRDV LMKLSGRIEC EGPNRHLYDF TGNLHLDGKS SVALGPDQIL LRGTQLRNTQ
WVFGVVVYTG HDSKLMQNST KAPLKRSNVE KVTNVQILVL FGILLVMALV SSVGALFWNG
SHGGKSWYIK KMDTNSDNFG YNLLTFIILY NNLIPISLLV TLEVVKYTQA LFINWDMDMY
YIENDTPAMA RTSNLNEELG QVKYLFSDKT GTLTCNIMNF KKCSIAGVTY GHFPELAREQ
SSDDFCRMTS CTNDSCDFND PRLLKNIEDQ HPTAPCIQEF LTLLAVCHTV VPEKDGDEII
YQASSPDEAA LVKGAKKLGF VFTGRTPYSV IIEAMGQEQT FGILNVLEFS SDRKRMSVIV
RLPSGQLRLY CKGADNVIFE RLSKDSKYME ETLCHLEYFA TEGLRTLCVA YADLSENEYE
EWLKVYQEAS IILKDRAQRL EECYEIIEKN LLLLGATAIE DRLQAGVPET IATLLKAEIK
IWVLTGDKQE TAINIGYSCR LVSQNMALIL LKEDSLDATR AAITQHCTDL GNLLGKENDV
ALIIDGHTLK YALSFEVRRS FLDLALSCKA VICCRVSPLQ KSEIVDVVKK RVKAITLAIG
DGANDVGMIQ TAHVGVGISG NEGMQATNNS DYAIAQFSYL EKLLLVHGAW SYNRVTKCIL
YCFYKNVVLY IIELWFAFVN GFSGQILFER WCIGLYNVIF TALPPFTLGI FERSCTQESM
LRFPQLYRIT QNAEGFNTKV FWGHCINALV HSLILFWVPM KALEHDTPVT SGHATDYLFV
GNIVYTYVVV TVCLKAGLET TAWTKFSHLA VWGSMLIWLV FFGVYSTIWP TIPIAPDMKG
QATMVLSSAY FWLGLFLVPT ACLIEDVAWR AAKHTCKKTL LEEVQELETK SRVMGKAMLR
DSNGKRMNER DRLIKRLSRK TPPTLFRTGS IQQCVSHGYA FSQEEHGAVT QEEIVRAYDT
TKENSRKK
