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 27-MAR-2024, entry version 138. 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}. 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; 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 EMDB; EMD-30636; -. DR SMR; Q9H6D3; -. DR BioGRID; 120423; 7. DR IntAct; Q9H6D3; 2. DR MINT; Q9H6D3; -. 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; 9606-ENSP00000362991; -. DR PeptideAtlas; Q9H6D3; -. DR ProteomicsDB; 80975; -. DR Antibodypedia; 55125; 85 antibodies from 20 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 AGR; HGNC:25508; -. DR CTD; 55113; -. DR DisGeNET; 55113; -. DR GeneCards; XKR8; -. DR HGNC; HGNC:25508; XKR8. DR HPA; ENSG00000158156; Low tissue specificity. DR MIM; 619940; gene. DR neXtProt; NX_Q9H6D3; -. DR OpenTargets; ENSG00000158156; -. DR PharmGKB; PA142670566; -. DR VEuPathDB; HostDB:ENSG00000158156; -. DR eggNOG; KOG4790; Eukaryota. DR GeneTree; ENSGT01090000260093; -. DR HOGENOM; CLU_028534_2_1_1; -. DR InParanoid; Q9H6D3; -. DR OMA; GYLYRCL; -. DR OrthoDB; 3385375at2759; -. DR PhylomeDB; Q9H6D3; -. DR TreeFam; TF316454; -. DR PathwayCommons; Q9H6D3; -. DR SignaLink; Q9H6D3; -. DR BioGRID-ORCS; 55113; 16 hits in 1159 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 208 other cell types or tissues. DR ExpressionAtlas; Q9H6D3; baseline and differential. 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 PANTHER; PTHR16024; XK-RELATED PROTEIN; 1. DR PANTHER; PTHR16024:SF8; XK-RELATED PROTEIN 8; 1. DR Pfam; PF09815; XK-related; 1. DR Genevisible; Q9H6D3; HS. 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 //