XKR4_MOUSE
ID XKR4_MOUSE Reviewed; 647 AA.
AC Q5GH67;
DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2005, sequence version 1.
DT 03-AUG-2022, entry version 106.
DE RecName: Full=XK-related protein 4 {ECO:0000305};
DE Contains:
DE RecName: Full=XK-related protein 4, processed form {ECO:0000305|PubMed:25231987};
GN Name=Xkr4 {ECO:0000312|MGI:MGI:3528744}; Synonyms=Xrg4 {ECO:0000303|Ref.1};
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=C57BL/6J;
RA Huang C.-H., Chen Y.;
RT "A superfamily of XK-related genes (XRG) widely expressed in vertebrates
RT and invertebrates.";
RL Submitted (JAN-2004) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain cortex;
RX PubMed=17114649; DOI=10.1074/mcp.m600046-mcp200;
RA Munton R.P., Tweedie-Cullen R., Livingstone-Zatchej M., Weinandy F.,
RA Waidelich M., Longo D., Gehrig P., Potthast F., Rutishauser D., Gerrits B.,
RA Panse C., Schlapbach R., Mansuy I.M.;
RT "Qualitative and quantitative analyses of protein phosphorylation in naive
RT and stimulated mouse synaptosomal preparations.";
RL Mol. Cell. Proteomics 6:283-293(2007).
RN [3]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-197, AND IDENTIFICATION BY
RP MASS 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 [4]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, SUBCELLULAR LOCATION,
RP PROTEOLYTIC CLEAVAGE, TISSUE SPECIFICITY, AND MUTAGENESIS OF ASP-564.
RX PubMed=25231987; DOI=10.1074/jbc.m114.583419;
RA Suzuki J., Imanishi E., Nagata S.;
RT "Exposure of phosphatidylserine by Xk-related protein family members during
RT apoptosis.";
RL J. Biol. Chem. 289:30257-30267(2014).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, SUBUNIT, INTERACTION
RP WITH XRCC4, AND MUTAGENESIS OF ILE-322; LEU-331 AND GLN-332.
RX PubMed=33725486; DOI=10.1016/j.molcel.2021.02.025;
RA Maruoka M., Zhang P., Mori H., Imanishi E., Packwood D.M., Harada H.,
RA Kosako H., Suzuki J.;
RT "Caspase cleavage releases a nuclear protein fragment that stimulates
RT phospholipid scrambling at the plasma membrane.";
RL Mol. Cell 81:1397-1410(2021).
CC -!- FUNCTION: [XK-related protein 4, processed form]: Phospholipid
CC scramblase that promotes phosphatidylserine exposure on apoptotic cell
CC surface (PubMed:25231987, PubMed:33725486). Phosphatidylserine is a
CC specific marker only present at the surface of apoptotic cells and acts
CC as a specific signal for engulfment (PubMed:25231987, PubMed:33725486).
CC {ECO:0000269|PubMed:25231987, ECO:0000269|PubMed:33725486}.
CC -!- CATALYTIC ACTIVITY: [XK-related protein 4, processed form]:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-L-serine(in) = a 1,2-diacyl-
CC sn-glycero-3-phospho-L-serine(out); Xref=Rhea:RHEA:38663,
CC ChEBI:CHEBI:57262; Evidence={ECO:0000305|PubMed:25231987,
CC ECO:0000305|PubMed:33725486};
CC -!- ACTIVITY REGULATION: Phospholipid scramblase activity is activated upon
CC caspase cleavage to generate the XK-related protein 4, processed form
CC (PubMed:25231987, PubMed:33725486). Does not act prior the onset of
CC apoptosis (PubMed:25231987). {ECO:0000269|PubMed:25231987,
CC ECO:0000269|PubMed:33725486}.
CC -!- ACTIVITY REGULATION: [XK-related protein 4, processed form]:
CC Homodimerizes upon caspase cleavage (PubMed:33725486). Phospholipid
CC scramblase activity is activated following interaction with the
CC processed C-terminus of XRCC4 (protein XRCC4, C-terminus)
CC (PubMed:33725486). {ECO:0000269|PubMed:33725486}.
CC -!- SUBUNIT: [XK-related protein 4, processed form]: Homodimer;
CC homodimerization takes place upon caspase cleavage (PubMed:33725486).
CC Interacts with the processed C-terminus of XRCC4 (protein XRCC4, C-
CC terminus); interaction promotes the phospholipid scramblase activity
CC (PubMed:33725486). {ECO:0000269|PubMed:33725486}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:25231987};
CC Multi-pass membrane protein {ECO:0000255}.
CC -!- TISSUE SPECIFICITY: Highly expressed in expressed in the brain; weakly
CC expressed in the spleen, thymus, uterus, blood vessels and fetus.
CC {ECO:0000269|PubMed:25231987}.
CC -!- PTM: [XK-related protein 4, processed form]: Undergoes proteolytic
CC processing by caspase-3 (CASP3), caspase-6 (CASP6) and caspase-7
CC (CASP7) to generate the XK-related protein 4, processed form, leading
CC to its activation. {ECO:0000269|PubMed:25231987}.
CC -!- SIMILARITY: Belongs to the XK family. {ECO:0000305}.
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DR EMBL; AY534250; AAT07099.1; -; mRNA.
DR CCDS; CCDS14803.1; -.
DR RefSeq; NP_001011874.1; NM_001011874.1.
DR RefSeq; XP_006495613.1; XM_006495550.3.
DR AlphaFoldDB; Q5GH67; -.
DR SMR; Q5GH67; -.
DR STRING; 10090.ENSMUSP00000070648; -.
DR iPTMnet; Q5GH67; -.
DR PhosphoSitePlus; Q5GH67; -.
DR SwissPalm; Q5GH67; -.
DR MaxQB; Q5GH67; -.
DR PaxDb; Q5GH67; -.
DR PeptideAtlas; Q5GH67; -.
DR PRIDE; Q5GH67; -.
DR ProteomicsDB; 300185; -.
DR Antibodypedia; 11703; 85 antibodies from 17 providers.
DR DNASU; 497097; -.
DR Ensembl; ENSMUST00000070533; ENSMUSP00000070648; ENSMUSG00000051951.
DR GeneID; 497097; -.
DR KEGG; mmu:497097; -.
DR UCSC; uc007aeu.1; mouse.
DR CTD; 114786; -.
DR MGI; MGI:3528744; Xkr4.
DR VEuPathDB; HostDB:ENSMUSG00000051951; -.
DR eggNOG; KOG4790; Eukaryota.
DR GeneTree; ENSGT00990000203579; -.
DR HOGENOM; CLU_028534_1_0_1; -.
DR InParanoid; Q5GH67; -.
DR OMA; SDGRRKM; -.
DR OrthoDB; 1230316at2759; -.
DR PhylomeDB; Q5GH67; -.
DR TreeFam; TF316454; -.
DR BioGRID-ORCS; 497097; 3 hits in 73 CRISPR screens.
DR ChiTaRS; Xkr4; mouse.
DR PRO; PR:Q5GH67; -.
DR Proteomes; UP000000589; Chromosome 1.
DR RNAct; Q5GH67; protein.
DR Bgee; ENSMUSG00000051951; Expressed in dentate gyrus of hippocampal formation granule cell and 31 other tissues.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016020; C:membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0017128; F:phospholipid scramblase activity; IDA:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:1902742; P:apoptotic process involved in development; IBA:GO_Central.
DR GO; GO:0043652; P:engulfment of apoptotic cell; IBA:GO_Central.
DR GO; GO:0070782; P:phosphatidylserine exposure on apoptotic cell surface; IDA:UniProtKB.
DR InterPro; IPR018629; XK-rel.
DR Pfam; PF09815; XK-related; 1.
PE 1: Evidence at protein level;
KW Apoptosis; Cell membrane; Membrane; Phosphoprotein; Reference proteome;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1..647
FT /note="XK-related protein 4"
FT /id="PRO_0000190778"
FT CHAIN 1..564
FT /note="XK-related protein 4, processed form"
FT /evidence="ECO:0000305|PubMed:25231987"
FT /id="PRO_0000453290"
FT TRANSMEM 112..132
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 142..162
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 245..265
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 303..323
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 328..348
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 362..382
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 393..415
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 425..445
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 454..474
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 484..504
FT /note="Helical"
FT /evidence="ECO:0000255"
FT REGION 1..44
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 197..238
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 17..35
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 207..238
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 564..565
FT /note="Cleavage; by caspase-3, caspase-6 and caspase-7"
FT /evidence="ECO:0000305|PubMed:25231987"
FT MOD_RES 197
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MUTAGEN 322
FT /note="I->S: Displays constitutive phospholipid scramblase
FT activity."
FT /evidence="ECO:0000269|PubMed:33725486"
FT MUTAGEN 331
FT /note="L->F: Displays constitutive phospholipid scramblase
FT activity."
FT /evidence="ECO:0000269|PubMed:33725486"
FT MUTAGEN 332
FT /note="Q->E: Displays constitutive phospholipid scramblase
FT activity."
FT /evidence="ECO:0000269|PubMed:33725486"
FT MUTAGEN 564
FT /note="D->A: In 1DA mutant; abolished cleavage by caspase,
FT preventing phospholipid scramblase activity."
FT /evidence="ECO:0000269|PubMed:25231987"
SQ SEQUENCE 647 AA; 71503 MW; 1E3E0D073E983231 CRC64;
MAAKSDGRLK MKKSSDVAFT PLQNSDNSGS VQGLAPGLPS GSGAEDTEAA GGGCCPDGGG
CSRCCCCCAG SGGSAGSGGS GGGGRGSGAG SAALCLRLGR EQRRYSLWDC LWILAAVAVY
FADVGTDIWL AVDYYLRGQR WWFGLTLFFV VLGSLSVQVF SFRWFVHDFS TEDSSTTTTS
SCQQPGADCK TVVSSGSAAG EGEVRPSTPQ RQASNASKSN IAATNSGSNS NGATRTSGKH
RSASCSFCIW LLQSLIHILQ LGQIWRYLHT IYLGIRSRQS GESGRWRFYW KMVYEYADVS
MLHLLATFLE SAPQLVLQLC IIVQTHSLQA LQGFTAAASL VSLAWALASY QKALRDSRDD
KKPISYMAVI IQFCWHFFTI AARVITFALF ASVFQLYFGI FIVLHWCIMT FWIVHCETEF
CITKWEEIVF DMVVGIIYIF SWFNVKEGRT RCRLFIYYFV ILLENTALSA LWYLYKAPQI
ADAFAIPALC VVFSSFLTGV VFMLMYYAFF HPNGPRFGQS PSCACDDPAT AFSLPPEVAT
STLRSISNNR SVASDRDQKF AERDGCVPVF QVRPTAPPTP SSRPPRIEES VIKIDLFRNR
YPAWERHVLD RSLRKAILAF ECSPSPPRLQ YKDDALIQER LEYETTL
