ID   XK_HUMAN                Reviewed;         444 AA.
AC   P51811; Q4TTN6; Q8IUK6; Q9UC77;
DT   01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT   24-JAN-2006, sequence version 5.
DT   27-MAR-2024, entry version 177.
DE   RecName: Full=Endoplasmic reticulum membrane adapter protein XK {ECO:0000305};
DE   AltName: Full=Kell complex 37 kDa component {ECO:0000303|PubMed:9593744};
DE   AltName: Full=Kx antigen {ECO:0000303|PubMed:8004674};
DE   AltName: Full=Membrane transport protein XK {ECO:0000305};
DE   AltName: Full=XK-related protein 1;
GN   Name=XK {ECO:0000303|PubMed:8004674, ECO:0000312|HGNC:HGNC:12811};
GN   Synonyms=XKR1, XRG1 {ECO:0000303|Ref.3};
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], AND TISSUE SPECIFICITY.
RX   PubMed=8004674; DOI=10.1016/0092-8674(94)90136-8;
RA   Ho M., Chelly J., Carter N., Danek A., Crocker P., Monaco A.P.;
RT   "Isolation of the gene for McLeod syndrome that encodes a novel membrane
RT   transport protein.";
RL   Cell 77:869-880(1994).
RN   [2]
RP   SEQUENCE REVISION TO 204-205.
RA   Ho M.;
RL   Submitted (MAY-1999) to the EMBL/GenBank/DDBJ databases.
RN   [3]
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   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG   SeattleSNPs variation discovery resource;
RL   Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Testis;
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   [6]
RP   PROTEIN SEQUENCE OF 1-22, AND LACK OF GLYCOSYLATION.
RX   PubMed=7737196; DOI=10.1111/j.1432-1033.1995.tb20342.x;
RA   Khamlichi S., Bailly P., Blanchard D., Goossens D., Cartron J.-P.,
RA   Bertrand O.;
RT   "Purification and partial characterization of the erythrocyte Kx protein
RT   deficient in McLeod patients.";
RL   Eur. J. Biochem. 228:931-934(1995).
RN   [7]
RP   SUBUNIT, SUBCELLULAR LOCATION, DISULFIDE BOND, MUTAGENESIS OF CYS-347, AND
RP   POLYMORPHISM.
RX   PubMed=9593744; DOI=10.1074/jbc.273.22.13950;
RA   Russo D., Redman C., Lee S.;
RT   "Association of XK and Kell blood group proteins.";
RL   J. Biol. Chem. 273:13950-13956(1998).
RN   [8]
RP   FUNCTION, INTERACTION WITH VPS13A, AND SUBCELLULAR LOCATION.
RX   PubMed=32845802; DOI=10.1091/mbc.e19-08-0439-t;
RA   Park J.S., Neiman A.M.;
RT   "XK is a partner for VPS13A: a molecular link between Chorea-Acanthocytosis
RT   and McLeod Syndrome.";
RL   Mol. Biol. Cell 31:2425-2436(2020).
RN   [9]
RP   VARIANT MLS ARG-294.
RX   PubMed=11761473; DOI=10.1002/ana.10035;
RA   Danek A., Rubio J.P., Rampoldi L., Ho M., Dobson-Stone C., Tison F.,
RA   Symmans W.A., Oechsner M., Kalckreuth W., Watt J.M., Corbett A.J.,
RA   Hamdalla H.H., Marshall A.G., Sutton I., Dotti M.T., Malandrini A.,
RA   Walker R.H., Daniels G., Monaco A.P.;
RT   "McLeod neuroacanthocytosis: genotype and phenotype.";
RL   Ann. Neurol. 50:755-764(2001).
RN   [10]
RP   VARIANT MLS GLY-222.
RX   PubMed=11961232; DOI=10.1046/j.1537-2995.2002.00049.x;
RA   Russo D.C., Lee S., Reid M.E., Redman C.M.;
RT   "Point mutations causing the McLeod phenotype.";
RL   Transfusion 42:287-293(2002).
RN   [11]
RP   VARIANT MLS LYS-327.
RX   PubMed=12823753; DOI=10.1046/j.1537-2995.2003.t01-1-00434.x;
RA   Jung H.H., Hergersberg M., Vogt M., Pahnke J., Treyer V., Rothlisberger B.,
RA   Kollias S.S., Russo D., Frey B.M.;
RT   "McLeod phenotype associated with a XK missense mutation without
RT   hematologic, neuromuscular, or cerebral involvement.";
RL   Transfusion 43:928-938(2003).
RN   [12]
RP   INVOLVEMENT IN MCLEOD SYNDROME, INTERACTION WITH VPS13A, VARIANT MLS
RP   124-GLN--ALA-444 DEL, AND VARIANT MLS 133-ARG--ALA-444 DEL.
RX   PubMed=31086825; DOI=10.1212/nxg.0000000000000328;
RA   Urata Y., Nakamura M., Sasaki N., Shiokawa N., Nishida Y., Arai K.,
RA   Hiwatashi H., Yokoyama I., Narumi S., Terayama Y., Murakami T., Ugawa Y.,
RA   Sakamoto H., Kaneko S., Nakazawa Y., Yamasaki R., Sadashima S., Sakai T.,
RA   Arai H., Sano A.;
RT   "Novel pathogenic XK mutations in McLeod syndrome and interaction between
RT   XK protein and chorein.";
RL   Neurol. Genet. 5:e328-e328(2019).
CC   -!- FUNCTION: Recruits the lipid transfer protein VPS13A from lipid
CC       droplets to the endoplasmic reticulum (ER) membrane.
CC       {ECO:0000269|PubMed:32845802}.
CC   -!- SUBUNIT: Heterodimer with Kell; disulfide-linked (PubMed:9593744).
CC       Interacts with VPS13A (PubMed:32845802, PubMed:31086825).
CC       {ECO:0000269|PubMed:31086825, ECO:0000269|PubMed:32845802,
CC       ECO:0000269|PubMed:9593744}.
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC       {ECO:0000269|PubMed:32845802, ECO:0000269|PubMed:9593744}; Multi-pass
CC       membrane protein {ECO:0000255}.
CC   -!- TISSUE SPECIFICITY: High levels in skeletal muscle, heart, brain, and
CC       pancreas; low levels in placenta, lung, liver, and kidney.
CC       {ECO:0000269|PubMed:8004674}.
CC   -!- PTM: Not glycosylated. {ECO:0000269|PubMed:7737196}.
CC   -!- POLYMORPHISM: XK is responsible for the Kx blood group system.
CC       {ECO:0000305|PubMed:9593744}.
CC   -!- DISEASE: McLeod syndrome (MLS) [MIM:300842]: A multisystem disorder
CC       characterized by the absence of red blood cell Kx antigen, weak
CC       expression of Kell red blood cell antigens, acanthocytosis, and
CC       compensated hemolysis. Most carriers of this McLeod blood group
CC       phenotype have acanthocytosis and elevated serum creatine kinase levels
CC       and are prone to develop a severe neurologic disorder resembling
CC       Huntington disease. Additional symptoms include generalized seizures,
CC       neuromuscular symptoms leading to weakness and atrophy, and
CC       cardiomyopathy mainly manifesting with atrial fibrillation, malignant
CC       arrhythmias, and dilated cardiomyopathy. {ECO:0000269|PubMed:11761473,
CC       ECO:0000269|PubMed:11961232, ECO:0000269|PubMed:12823753,
CC       ECO:0000269|PubMed:31086825}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- SIMILARITY: Belongs to the XK family. {ECO:0000305}.
CC   -!- WEB RESOURCE: Name=SeattleSNPs;
CC       URL="http://pga.gs.washington.edu/data/xk/";
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DR   EMBL; Z32684; CAA83632.2; -; mRNA.
DR   EMBL; AY534238; AAT07087.1; -; mRNA.
DR   EMBL; DQ062746; AAY43132.1; -; Genomic_DNA.
DR   EMBL; BC036019; AAH36019.1; -; mRNA.
DR   CCDS; CCDS14241.1; -.
DR   PIR; I39294; I39294.
DR   RefSeq; NP_066569.1; NM_021083.3.
DR   AlphaFoldDB; P51811; -.
DR   SMR; P51811; -.
DR   BioGRID; 113341; 10.
DR   IntAct; P51811; 1.
DR   STRING; 9606.ENSP00000367879; -.
DR   TCDB; 2.A.112.1.1; the kx blood-group antigen (kxa) family.
DR   iPTMnet; P51811; -.
DR   PhosphoSitePlus; P51811; -.
DR   SwissPalm; P51811; -.
DR   BioMuta; XK; -.
DR   DMDM; 85700269; -.
DR   EPD; P51811; -.
DR   jPOST; P51811; -.
DR   MassIVE; P51811; -.
DR   MaxQB; P51811; -.
DR   PaxDb; 9606-ENSP00000367879; -.
DR   PeptideAtlas; P51811; -.
DR   ProteomicsDB; 56407; -.
DR   Antibodypedia; 10552; 188 antibodies from 27 providers.
DR   DNASU; 7504; -.
DR   Ensembl; ENST00000378616.5; ENSP00000367879.3; ENSG00000047597.7.
DR   GeneID; 7504; -.
DR   KEGG; hsa:7504; -.
DR   MANE-Select; ENST00000378616.5; ENSP00000367879.3; NM_021083.4; NP_066569.1.
DR   UCSC; uc004ddq.4; human.
DR   AGR; HGNC:12811; -.
DR   CTD; 7504; -.
DR   DisGeNET; 7504; -.
DR   GeneCards; XK; -.
DR   GeneReviews; XK; -.
DR   HGNC; HGNC:12811; XK.
DR   HPA; ENSG00000047597; Tissue enhanced (bone marrow, intestine, stomach).
DR   MalaCards; XK; -.
DR   MIM; 300842; phenotype.
DR   MIM; 314850; gene.
DR   neXtProt; NX_P51811; -.
DR   OpenTargets; ENSG00000047597; -.
DR   Orphanet; 59306; McLeod neuroacanthocytosis syndrome.
DR   PharmGKB; PA37410; -.
DR   VEuPathDB; HostDB:ENSG00000047597; -.
DR   eggNOG; ENOG502QTTF; Eukaryota.
DR   GeneTree; ENSGT00390000003231; -.
DR   HOGENOM; CLU_037429_1_1_1; -.
DR   InParanoid; P51811; -.
DR   OMA; SGGDGMW; -.
DR   OrthoDB; 5265454at2759; -.
DR   PhylomeDB; P51811; -.
DR   TreeFam; TF331465; -.
DR   PathwayCommons; P51811; -.
DR   Reactome; R-HSA-375276; Peptide ligand-binding receptors.
DR   SABIO-RK; P51811; -.
DR   SignaLink; P51811; -.
DR   BioGRID-ORCS; 7504; 6 hits in 772 CRISPR screens.
DR   ChiTaRS; XK; human.
DR   GenomeRNAi; 7504; -.
DR   Pharos; P51811; Tbio.
DR   PRO; PR:P51811; -.
DR   Proteomes; UP000005640; Chromosome X.
DR   RNAct; P51811; Protein.
DR   Bgee; ENSG00000047597; Expressed in trabecular bone tissue and 154 other cell types or tissues.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR   GO; GO:0016020; C:membrane; TAS:HGNC-UCL.
DR   GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR   GO; GO:0030674; F:protein-macromolecule adaptor activity; IMP:UniProtKB.
DR   GO; GO:0006865; P:amino acid transport; IEA:UniProtKB-KW.
DR   GO; GO:0006874; P:intracellular calcium ion homeostasis; IEA:Ensembl.
DR   GO; GO:0010961; P:intracellular magnesium ion homeostasis; IEA:Ensembl.
DR   GO; GO:0042552; P:myelination; IEA:Ensembl.
DR   GO; GO:0031133; P:regulation of axon diameter; IEA:Ensembl.
DR   GO; GO:0008361; P:regulation of cell size; IEA:Ensembl.
DR   GO; GO:0048741; P:skeletal muscle fiber development; IEA:Ensembl.
DR   InterPro; IPR018629; XK-rel.
DR   PANTHER; PTHR14297:SF8; ENDOPLASMIC RETICULUM MEMBRANE ADAPTER PROTEIN XK; 1.
DR   PANTHER; PTHR14297; MEMBRANE TRANSPORT PROTEIN XK FAMILY MEMBER; 1.
DR   Pfam; PF09815; XK-related; 1.
DR   Genevisible; P51811; HS.
PE   1: Evidence at protein level;
KW   Amino-acid transport; Blood group antigen; Direct protein sequencing;
KW   Disease variant; Disulfide bond; Endoplasmic reticulum; Membrane;
KW   Phosphoprotein; Reference proteome; Transmembrane; Transmembrane helix;
KW   Transport.
FT   CHAIN           1..444
FT                   /note="Endoplasmic reticulum membrane adapter protein XK"
FT                   /id="PRO_0000190767"
FT   TOPO_DOM        1..2
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        3..23
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        24..37
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        38..58
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        59..68
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        69..89
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        90..140
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        141..161
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        162..171
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        172..192
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        193..208
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        209..229
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        230..235
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        236..256
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        257..277
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        278..298
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        299..317
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        318..338
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        339..349
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        350..370
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        371..444
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   REGION          408..444
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        408..425
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         115
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q5GH61"
FT   DISULFID        347
FT                   /note="Interchain (with C-72 in Kell)"
FT                   /evidence="ECO:0000269|PubMed:9593744"
FT   VARIANT         124..444
FT                   /note="Missing (in MLS)"
FT                   /evidence="ECO:0000269|PubMed:31086825"
FT                   /id="VAR_086162"
FT   VARIANT         133..444
FT                   /note="Missing (in MLS)"
FT                   /evidence="ECO:0000269|PubMed:31086825"
FT                   /id="VAR_086163"
FT   VARIANT         222
FT                   /note="R -> G (in MLS)"
FT                   /evidence="ECO:0000269|PubMed:11961232"
FT                   /id="VAR_013817"
FT   VARIANT         294
FT                   /note="C -> R (in MLS; dbSNP:rs28933690)"
FT                   /evidence="ECO:0000269|PubMed:11761473"
FT                   /id="VAR_013818"
FT   VARIANT         327
FT                   /note="E -> K (in MLS; atypical without hematologic,
FT                   neuromuscular, or cerebral involvement)"
FT                   /evidence="ECO:0000269|PubMed:12823753"
FT                   /id="VAR_023581"
FT   MUTAGEN         347
FT                   /note="C->S: Loss of Kell-XK complex."
FT                   /evidence="ECO:0000269|PubMed:9593744"
FT   CONFLICT        248
FT                   /note="F -> L (in Ref. 3 and 5)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   444 AA;  50902 MW;  6F90B0B45659A1DA CRC64;
     MKFPASVLAS VFLFVAETTA ALSLSSTYRS GGDRMWQALT LLFSLLPCAL VQLTLLFVHR
     DLSRDRPLVL LLHLLQLGPL FRCFEVFCIY FQSGNNEEPY VSITKKRQMP KNGLSEEIEK
     EVGQAEGKLI THRSAFSRAS VIQAFLGSAP QLTLQLYISV MQQDVTVGRS LLMTISLLSI
     VYGALRCNIL AIKIKYDEYE VKVKPLAYVC IFLWRSFEIA TRVVVLVLFT SVLKTWVVVI
     ILINFFSFFL YPWILFWCSG SPFPENIEKA LSRVGTTIVL CFLTLLYTGI NMFCWSAVQL
     KIDSPDLISK SHNWYQLLVY YMIRFIENAI LLLLWYLFKT DIYMYVCAPL LVLQLLIGYC
     TAILFMLVFY QFFHPCKKLF SSSVSEGFQR WLRCFCWACR QQKPCEPIGK EDLQSSRDRD
     ETPSSSKTSP EPGQFLNAED LCSA
//