XKR8_HUMAN
ID XKR8_HUMAN Reviewed; 395 AA.
AC Q9H6D3;
DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2001, sequence version 1.
DT 03-AUG-2022, entry version 130.
DE RecName: Full=XK-related protein 8 {ECO:0000305};
DE Short=hXkr8 {ECO:0000303|PubMed:23845944};
DE Contains:
DE RecName: Full=XK-related protein 8, processed form {ECO:0000305|PubMed:23845944};
GN Name=XKR8 {ECO:0000303|PubMed:23845944, ECO:0000312|HGNC:HGNC:25508};
GN Synonyms=XRG8 {ECO:0000303|Ref.1};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
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 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skin;
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 PROTEIN SEQUENCE OF 2-6, FUNCTION, AND CATALYTIC ACTIVITY.
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 [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [7]
RP FUNCTION, SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING BY CASP3, AND
RP MUTAGENESIS OF 352-ASP--ASP-355.
RX PubMed=23845944; DOI=10.1126/science.1236758;
RA Suzuki J., Denning D.P., Imanishi E., Horvitz H.R., Nagata S.;
RT "Xk-Related protein 8 and CED-8 promote phosphatidylserine exposure in
RT apoptotic cells.";
RL Science 341:403-406(2013).
RN [8]
RP SUBCELLULAR LOCATION, SUBUNIT, INTERACTION WITH BSG AND NPTN, AND
RP MUTAGENESIS OF 352-ASP--ASP-355.
RX PubMed=27503893; DOI=10.1073/pnas.1610403113;
RA Suzuki J., Imanishi E., Nagata S.;
RT "Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine
RT exposure.";
RL Proc. Natl. Acad. Sci. U.S.A. 113:9509-9514(2016).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF 352-ASP--ASP-355.
RX PubMed=28881496; DOI=10.1111/febs.14261;
RA Kim G.W., Nam G.H., Kim I.S., Park S.Y.;
RT "Xk-related protein 8 regulates myoblast differentiation and survival.";
RL FEBS J. 284:3575-3588(2017).
RN [10]
RP FUNCTION (MICROBIAL INFECTION).
RX PubMed=29338048; DOI=10.1371/journal.ppat.1006848;
RA Nanbo A., Maruyama J., Imai M., Ujie M., Fujioka Y., Nishide S., Takada A.,
RA Ohba Y., Kawaoka Y.;
RT "Ebola virus requires a host scramblase for externalization of
RT phosphatidylserine on the surface of viral particles.";
RL PLoS Pathog. 14:e1006848-e1006848(2018).
CC -!- FUNCTION: [XK-related protein 8, processed form]: Phospholipid
CC scramblase that promotes phosphatidylserine exposure on apoptotic cell
CC surface (PubMed:23845944, PubMed:25231987). Phosphatidylserine is a
CC specific marker only present at the surface of apoptotic cells and acts
CC as a specific signal for engulfment (PubMed:23845944). Required for the
CC clearance of apoptotic cells, such as engulfment of apoptotic germ
CC cells by Sertoli cells, clearance of senescent neutrophils or
CC regulation of bipolar cell numbers in the retina (By similarity). Has
CC no effect on calcium-induced exposure of phosphatidylserine
CC (PubMed:23845944). Promotes myoblast differentiation and survival
CC (PubMed:28881496). {ECO:0000250|UniProtKB:Q8C0T0,
CC ECO:0000269|PubMed:23845944, ECO:0000269|PubMed:25231987,
CC ECO:0000269|PubMed:28881496}.
CC -!- FUNCTION: (Microbial infection) Incorporated into Ebola virus-like
CC particles, where its phospholipid scramblase activity is required to
CC promote phosphatidylserine exposure on the surface of viral particles
CC (PubMed:29338048). Externalization of phosphatidylserine on the surface
CC of viral particles is required for uptake by host cells
CC (PubMed:29338048). {ECO:0000269|PubMed:29338048}.
CC -!- CATALYTIC ACTIVITY: [XK-related protein 8, 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:23845944,
CC ECO:0000305|PubMed:25231987};
CC -!- ACTIVITY REGULATION: Activated upon caspase cleavage to generate the
CC XK-related protein 8, processed form (PubMed:23845944). Does not act
CC prior the onset of apoptosis (PubMed:23845944).
CC {ECO:0000269|PubMed:23845944}.
CC -!- SUBUNIT: Interacts with BSG and NPTN; which act as chaperones to
CC localize XKR8 at the cell membrane. {ECO:0000269|PubMed:27503893}.
CC -!- SUBUNIT: [XK-related protein 8, processed form]: Homodimer.
CC {ECO:0000305|PubMed:27503893}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:23845944,
CC ECO:0000269|PubMed:27503893, ECO:0000269|PubMed:28881496}; Multi-pass
CC membrane protein {ECO:0000255}. Cytoplasm, perinuclear region
CC {ECO:0000269|PubMed:28881496}.
CC -!- PTM: [XK-related protein 8]: Undergoes proteolytic processing by
CC caspase-3 (CASP3) to generate the XK-related protein 8, processed form,
CC leading to its activation. {ECO:0000269|PubMed:23845944}.
CC -!- PTM: Phosphorylation at Thr-375 activates the phospholipid scramblase
CC activity. {ECO:0000250|UniProtKB:Q8C0T0}.
CC -!- MISCELLANEOUS: Expression is repressed in PLB-985 leukemia and Raji
CC lymphoma cells due to CpG methylation near the transcription start site
CC of XKR8 gene, possibly explaining the inability of PLB-985 leukemia and
CC Raji lymphoma cells to expose phosphatidylserine during apoptosis.
CC {ECO:0000305|PubMed:23845944}.
CC -!- SIMILARITY: Belongs to the XK family. {ECO:0000305}.
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DR EMBL; AY534246; AAT07095.1; -; mRNA.
DR EMBL; AK026024; BAB15326.1; -; mRNA.
DR EMBL; AL512288; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC013379; AAH13379.1; -; mRNA.
DR EMBL; BC028564; AAH28564.1; -; mRNA.
DR CCDS; CCDS315.1; -.
DR RefSeq; NP_060523.2; NM_018053.3.
DR PDB; 7DCE; EM; 3.80 A; X=1-395.
DR PDBsum; 7DCE; -.
DR AlphaFoldDB; Q9H6D3; -.
DR SMR; Q9H6D3; -.
DR BioGRID; 120423; 6.
DR IntAct; Q9H6D3; 1.
DR STRING; 9606.ENSP00000362991; -.
DR TCDB; 2.A.112.1.13; the kx blood-group antigen (kxa) family.
DR iPTMnet; Q9H6D3; -.
DR BioMuta; XKR8; -.
DR DMDM; 74752693; -.
DR EPD; Q9H6D3; -.
DR MassIVE; Q9H6D3; -.
DR PaxDb; Q9H6D3; -.
DR PeptideAtlas; Q9H6D3; -.
DR PRIDE; Q9H6D3; -.
DR ProteomicsDB; 80975; -.
DR Antibodypedia; 55125; 80 antibodies from 19 providers.
DR DNASU; 55113; -.
DR Ensembl; ENST00000373884.6; ENSP00000362991.5; ENSG00000158156.9.
DR GeneID; 55113; -.
DR KEGG; hsa:55113; -.
DR MANE-Select; ENST00000373884.6; ENSP00000362991.5; NM_018053.4; NP_060523.2.
DR UCSC; uc001bph.2; human.
DR CTD; 55113; -.
DR DisGeNET; 55113; -.
DR GeneCards; XKR8; -.
DR HGNC; HGNC:25508; XKR8.
DR HPA; ENSG00000158156; Low tissue specificity.
DR neXtProt; NX_Q9H6D3; -.
DR OpenTargets; ENSG00000158156; -.
DR PharmGKB; PA142670566; -.
DR VEuPathDB; HostDB:ENSG00000158156; -.
DR eggNOG; KOG4790; Eukaryota.
DR GeneTree; ENSGT01050000244963; -.
DR HOGENOM; CLU_028534_2_1_1; -.
DR InParanoid; Q9H6D3; -.
DR OMA; GYLYRCL; -.
DR OrthoDB; 1230316at2759; -.
DR PhylomeDB; Q9H6D3; -.
DR TreeFam; TF316454; -.
DR PathwayCommons; Q9H6D3; -.
DR SignaLink; Q9H6D3; -.
DR BioGRID-ORCS; 55113; 15 hits in 1081 CRISPR screens.
DR GenomeRNAi; 55113; -.
DR Pharos; Q9H6D3; Tbio.
DR PRO; PR:Q9H6D3; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; Q9H6D3; protein.
DR Bgee; ENSG00000158156; Expressed in oocyte and 206 other tissues.
DR ExpressionAtlas; Q9H6D3; baseline and differential.
DR Genevisible; Q9H6D3; HS.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016020; C:membrane; IBA:GO_Central.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0017128; F:phospholipid scramblase 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; IDA:UniProtKB.
DR GO; GO:0051649; P:establishment of localization in cell; IEA:Ensembl.
DR GO; GO:0097350; P:neutrophil clearance; ISS:UniProtKB.
DR GO; GO:0070782; P:phosphatidylserine exposure on apoptotic cell surface; IDA:UniProtKB.
DR GO; GO:0045663; P:positive regulation of myoblast differentiation; IDA:UniProtKB.
DR GO; GO:0002513; P:tolerance induction to self antigen; IEA:Ensembl.
DR InterPro; IPR018629; XK-rel.
DR Pfam; PF09815; XK-related; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Apoptosis; Cell membrane; Cytoplasm;
KW Direct protein sequencing; Membrane; Phosphoprotein; Reference proteome;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1..395
FT /note="XK-related protein 8"
FT /id="PRO_0000190792"
FT CHAIN 1..355
FT /note="XK-related protein 8, processed form"
FT /evidence="ECO:0000305|PubMed:23845944"
FT /id="PRO_0000423984"
FT TOPO_DOM 1..12
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 13..33
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 34..47
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 48..68
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 69..158
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 159..179
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 180..200
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 201..221
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 222..223
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 224..244
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 245..259
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 260..277
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 278..284
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 285..305
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 306..312
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 313..333
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 334..395
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT SITE 355..356
FT /note="Cleavage; by caspase-3"
FT /evidence="ECO:0000305|PubMed:23845944"
FT MOD_RES 362
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8C0T0"
FT MOD_RES 375
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q8C0T0"
FT MUTAGEN 352..355
FT /note="DQVD->AQVA: In 2DA; abolished cleavage by CASP3 and
FT ability to promote phosphatidylserine exposure. Does not
FT affect interaction with BSG but prevents homodimerization.
FT Does not affect ability to promote myoblast
FT differentiation."
FT /evidence="ECO:0000269|PubMed:23845944,
FT ECO:0000269|PubMed:27503893, ECO:0000269|PubMed:28881496"
SQ SEQUENCE 395 AA; 44655 MW; 23199BAEEA6964C6 CRC64;
MPWSSRGALL RDLVLGVLGT AAFLLDLGTD LWAAVQYALG GRYLWAALVL ALLGLASVAL
QLFSWLWLRA DPAGLHGSQP PRRCLALLHL LQLGYLYRCV QELRQGLLVW QQEEPSEFDL
AYADFLALDI SMLRLFETFL ETAPQLTLVL AIMLQSGRAE YYQWVGICTS FLGISWALLD
YHRALRTCLP SKPLLGLGSS VIYFLWNLLL LWPRVLAVAL FSALFPSYVA LHFLGLWLVL
LLWVWLQGTD FMPDPSSEWL YRVTVATILY FSWFNVAEGR TRGRAIIHFA FLLSDSILLV
ATWVTHSSWL PSGIPLQLWL PVGCGCFFLG LALRLVYYHW LHPSCCWKPD PDQVDGARSL
LSPEGYQLPQ NRRMTHLAQK FFPKAKDEAA SPVKG
