CXCR4_HUMAN
ID CXCR4_HUMAN Reviewed; 352 AA.
AC P61073; B2R5N0; O60835; P30991; P56438; Q53S69; Q9BXA0; Q9UKN2;
DT 26-APR-2004, integrated into UniProtKB/Swiss-Prot.
DT 26-APR-2004, sequence version 1.
DT 03-AUG-2022, entry version 193.
DE RecName: Full=C-X-C chemokine receptor type 4;
DE Short=CXC-R4;
DE Short=CXCR-4;
DE AltName: Full=FB22;
DE AltName: Full=Fusin;
DE AltName: Full=HM89;
DE AltName: Full=LCR1;
DE AltName: Full=Leukocyte-derived seven transmembrane domain receptor;
DE Short=LESTR {ECO:0000303|PubMed:8276799};
DE AltName: Full=Lipopolysaccharide-associated protein 3;
DE Short=LAP-3;
DE Short=LPS-associated protein 3;
DE AltName: Full=NPYRL;
DE AltName: Full=Stromal cell-derived factor 1 receptor;
DE Short=SDF-1 receptor;
DE AltName: CD_antigen=CD184;
GN Name=CXCR4;
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] (ISOFORM 1), AND PRELIMINARY FUNCTION.
RC TISSUE=Lung;
RX PubMed=8329116; DOI=10.1089/dna.1993.12.465;
RA Herzog H., Hort Y.J., Shine J., Selbie L.A.;
RT "Molecular cloning, characterization, and localization of the human homolog
RT to the reported bovine NPY Y3 receptor: lack of NPY binding and
RT activation.";
RL DNA Cell Biol. 12:465-471(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PRELIMINARY FUNCTION.
RC TISSUE=Fetal brain;
RX PubMed=8234909; DOI=10.1016/0167-0115(93)90392-l;
RA Jazin E.E., Yoo H., Blomqvist A.G., Yee F., Weng G., Walker M.W., Salon J.,
RA Larhammar D., Wahlestedt C.R.;
RT "A proposed bovine neuropeptide Y (NPY) receptor cDNA clone, or its human
RT homologue, confers neither NPY binding sites nor NPY responsiveness on
RT transfected cells.";
RL Regul. Pept. 47:247-258(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Fetal spleen;
RX PubMed=8325644; DOI=10.1006/geno.1993.1251;
RA Federsppiel B., Melhado I.G., Duncan A.M.V., Delaney A.D., Schappert K.,
RA Clark-Lewis I., Jirik F.R.;
RT "Molecular cloning of the cDNA and chromosomal localization of the gene for
RT a putative seven-transmembrane segment (7-TMS) receptor isolated from human
RT spleen.";
RL Genomics 16:707-712(1993).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Monocyte;
RX PubMed=8276799; DOI=10.1016/s0021-9258(17)42339-8;
RA Loetscher M., Geiser T., O'Reilly T., Zwahlen R., Baggiolini M., Moser B.;
RT "Cloning of a human seven-transmembrane domain receptor, LESTR, that is
RT highly expressed in leukocytes.";
RL J. Biol. Chem. 269:232-237(1994).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=7505609; DOI=10.1093/intimm/5.10.1239;
RA Nomura H., Nielsen B.W., Matsushima K.;
RT "Molecular cloning of cDNAs encoding a LD78 receptor and putative leukocyte
RT chemotactic peptide receptors.";
RL Int. Immunol. 5:1239-1249(1993).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND CHARACTERIZATION OF ITS HIV-1
RP CORECEPTOR FUNCTION.
RX PubMed=8629022; DOI=10.1126/science.272.5263.872;
RA Feng Y., Broder C.C., Kennedy P.E., Berger E.A.;
RT "HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G
RT protein-coupled receptor.";
RL Science 272:872-877(1996).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Peripheral blood leukocyte;
RX PubMed=9468539; DOI=10.1074/jbc.273.8.4754;
RA Wegner S.A., Ehrenberg P.K., Chang G., Dayhoff D.E., Sleeker A.L.,
RA Michael N.L.;
RT "Genomic organization and functional characterization of the chemokine
RT receptor CXCR4, a major entry co-receptor for human immunodeficiency virus
RT type 1.";
RL J. Biol. Chem. 273:4754-4760(1998).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9599023; DOI=10.1016/s0014-5793(98)00359-7;
RA Caruz A., Samsom M., Alonso J.M., Alcami J., Baleux F., Virelizier J.-L.,
RA Parmentier M., Arenzana-Seisdedos F.;
RT "Genomic organization and promoter characterization of human CXCR4 gene.";
RL FEBS Lett. 426:271-278(1998).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=10480633; DOI=10.1089/088922299310296;
RA Xiao L., Weiss S.H., Qari S.H., Rudolph D., Zhao C., Denny T.N., Hodge T.,
RA Lal R.B.;
RT "Partial resistance to infection by R5X4 primary HIV type 1 isolates in an
RT exposed-uninfected individual homozygous for CCR5 32-base pair deletion.";
RL AIDS Res. Hum. Retroviruses 15:1201-1208(1999).
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Peripheral blood lymphocyte;
RX PubMed=9879064; DOI=10.3109/10799899809047750;
RA Frodl R., Gierschik P., Moepps B.;
RT "Genomic organization and expression of the CXCR4 gene in mouse and man:
RT absence of a splice variant corresponding to mouse CXCR4-B in human
RT tissues.";
RL J. Recept. Signal Transduct. 18:321-344(1998).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, AND SUBCELLULAR LOCATION.
RC TISSUE=Neutrophil;
RX PubMed=10452968;
RA Gupta S.K., Pillarisetti K.;
RT "CXCR4-Lo: molecular cloning and functional expression of a novel human
RT CXCR4 splice variant.";
RL J. Immunol. 163:2368-2372(1999).
RN [12]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Fan Z., Li T., Li J., Luo B.;
RL Submitted (FEB-2001) to the EMBL/GenBank/DDBJ databases.
RN [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Adrenal gland;
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 [14]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung;
RA Warren C.N., Aronstam R.S., Sharma S.V.;
RT "cDNA clones of human proteins involved in signal transduction sequenced by
RT the Guthrie cDNA resource center (www.cdna.org).";
RL Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases.
RN [15]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [16]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG SeattleSNPs variation discovery resource;
RL Submitted (AUG-2004) to the EMBL/GenBank/DDBJ databases.
RN [17]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [18]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [19]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Colon;
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 [20]
RP FUNCTION.
RX PubMed=8752280; DOI=10.1038/382829a0;
RA Bleul C.C., Farzan M., Choe H., Parolin C., Clark-Lewis I., Sodroski J.,
RA Springer T.A.;
RT "The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and
RT blocks HIV-1 entry.";
RL Nature 382:829-833(1996).
RN [21]
RP FUNCTION.
RX PubMed=8752281; DOI=10.1038/382833a0;
RA Oberlin E., Amara A., Bachelerie F., Bessia C., Virelizier J.-L.,
RA Arenzana-Seisdedos F., Schwartz O., Heard J.-M., Clark-Lewis I.,
RA Legler D.F., Loetscher M., Baggiolini M., Moser B.;
RT "The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents
RT infection by T-cell-line-adapted HIV-1.";
RL Nature 382:833-835(1996).
RN [22]
RP ERRATUM OF PUBMED:8752281.
RA Oberlin E., Amara A., Bachelerie F., Bessia C., Virelizier J.-L.,
RA Arenzana-Seisdedos F., Schwartz O., Heard J.-M., Clark-Lewis I.,
RA Legler D.F., Loetscher M., Baggiolini M., Moser B.;
RL Nature 384:288-288(1996).
RN [23]
RP FUNCTION (MICROBIAL INFECTION), AND CHARACTERIZATION AS HIV-1 CORECEPTOR.
RX PubMed=8849450; DOI=10.1126/science.274.5287.602;
RA Lapham C.K., Ouyang J., Chandrasekhar B., Nguyen N.Y., Dimitrov D.S.,
RA Golding H.;
RT "Evidence for cell-surface association between fusin and the CD4-gp120
RT complex in human cell lines.";
RL Science 274:602-605(1996).
RN [24]
RP FUNCTION (MICROBIAL INFECTION), AND CHARACTERIZATION AS HIV-2 PRIMARY
RP RECEPTOR IN SOME ISOLATES.
RX PubMed=8929542; DOI=10.1016/s0092-8674(00)81393-8;
RA Endres M.J., Clapham P.R., Marsh M., Ahuja M., Turner J.D., McKnight A.,
RA Thomas J.F., Stoebenau-Haggarty B., Choe S., Vance P.J., Wells T.N.C.,
RA Power C.A., Sutterwala S.S., Doms R.W., Landau N.R., Hoxie J.A.;
RT "CD4-independent infection by HIV-2 is mediated by fusin/CXCR4.";
RL Cell 87:745-756(1996).
RN [25]
RP ANTAGONIST, INTERACTION WITH CXCL12, FUNCTION (MICROBIAL INFECTION), AND
RP CHARACTERIZATION AS HIV-1 CORECEPTOR.
RX PubMed=9427609; DOI=10.1038/nm0198-072;
RA Donzella G.A., Schols D., Lin S.W., Este J.A., Nagashima K.A., Maddon P.J.,
RA Allaway G.P., Sakmar T.P., Henson G., De Clercq E., Moore J.P.;
RT "AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-
RT receptor.";
RL Nat. Med. 4:72-77(1998).
RN [26]
RP SULFATION.
RX PubMed=10089882; DOI=10.1016/s0092-8674(00)80577-2;
RA Farzan M., Mirzabekov T., Kolchinsky P., Wyatt R., Cayabyab M.,
RA Gerard N.P., Gerard C., Sodroski J., Choe H.;
RT "Tyrosine sulfation of the amino terminus of CCR5 facilitates HIV-1
RT entry.";
RL Cell 96:667-676(1999).
RN [27]
RP FUNCTION, AND MUTAGENESIS OF ARG-183; ARG-188 AND ASP-193.
RX PubMed=10074102; DOI=10.1128/jvi.73.4.2576-2586.1999;
RA Brelot A., Heveker N., Adema K., Hosie M.J., Willett B., Alizon M.;
RT "Effect of mutations in the second extracellular loop of CXCR4 on its
RT utilization by human and feline immunodeficiency viruses.";
RL J. Virol. 73:2576-2586(1999).
RN [28]
RP DOMAINS, FUNCTION (MICROBIAL INFECTION), AND INTERACTION WITH HIV-1 SURFACE
RP PROTEIN GP120.
RX PubMed=10074122; DOI=10.1128/jvi.73.4.2752-2761.1999;
RA Doranz B.J., Orsini M.J., Turner J.D., Hoffman T.L., Berson J.F.,
RA Hoxie J.A., Peiper S.C., Brass L.F., Doms R.W.;
RT "Identification of CXCR4 domains that support coreceptor and chemokine
RT receptor functions.";
RL J. Virol. 73:2752-2761(1999).
RN [29]
RP INTERACTION WITH ARRB2, AND FUNCTION.
RX PubMed=10644702; DOI=10.1074/jbc.275.4.2479;
RA Cheng Z.J., Zhao J., Sun Y., Hu W., Wu Y.L., Cen B., Wu G.-X., Pei G.;
RT "beta-arrestin differentially regulates the chemokine receptor CXCR4-
RT mediated signaling and receptor internalization, and this implicates
RT multiple interaction sites between beta-arrestin and CXCR4.";
RL J. Biol. Chem. 275:2479-2485(2000).
RN [30]
RP FUNCTION, INTERACTION WITH CXCL12, AND MUTAGENESIS OF 2-GLU--SER-9;
RP 4-ILE--ASP-20; TYR-7; 10-ASP--ASP-20; TYR-12; 14-GLU-GLU-15; TYR-21;
RP ASP-97; ASP-171; ASP-187; ASP-193; ASP-262; GLU-268 AND GLU-288.
RX PubMed=10825158; DOI=10.1074/jbc.m000776200;
RA Brelot A., Heveker N., Montes M., Alizon M.;
RT "Identification of residues of CXCR4 critical for human immunodeficiency
RT virus coreceptor and chemokine receptor activities.";
RL J. Biol. Chem. 275:23736-23744(2000).
RN [31]
RP GLYCOSYLATION AT ASN-11, FUNCTION (MICROBIAL INFECTION), INTERACTION WITH
RP HIV-1 ENV, SUBUNIT, AND MUTAGENESIS OF ASN-11; THR-13 AND ASN-176.
RX PubMed=10756055; DOI=10.1128/jvi.74.9.4404-4413.2000;
RA Chabot D.J., Chen H., Dimitrov D.S., Broder C.C.;
RT "N-linked glycosylation of CXCR4 masks coreceptor function for CCR5-
RT dependent human immunodeficiency virus type 1 isolates.";
RL J. Virol. 74:4404-4413(2000).
RN [32]
RP INDUCTION (MICROBIAL INFECTION), AND INTERACTION WITH HIV-1 TAT.
RX PubMed=11027346; DOI=10.1073/pnas.97.21.11466;
RA Xiao H., Neuveut C., Tiffany H.L., Benkirane M., Rich E.A., Murphy P.M.,
RA Jeang K.-T.;
RT "Selective CXCR4 antagonism by Tat: implications for in vivo expansion of
RT coreceptor use by HIV-1.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:11466-11471(2000).
RN [33]
RP FUNCTION, IDENTIFICATION AS LPS RECEPTOR, INTERACTION WITH GDF5; HSP90AA1
RP AND HSPA8, AND TISSUE SPECIFICITY.
RX PubMed=11276205; DOI=10.1038/86342;
RA Triantafilou K., Triantafilou M., Dedrick R.L.;
RT "A CD14-independent LPS receptor cluster.";
RL Nat. Immunol. 2:338-345(2001).
RN [34]
RP GLYCOSYLATION AT SER-18, IDENTIFICATION OF PROTEOGLYCAN, INTERACTION WITH
RP CXCL12, SULFATION AT TYR-21, AND MUTAGENESIS OF TYR-7; THR-8; SER-9;
RP TYR-12; SER-18 AND TYR-21.
RX PubMed=12034737; DOI=10.1074/jbc.m203361200;
RA Farzan M., Babcock G.J., Vasilieva N., Wright P.L., Kiprilov E.,
RA Mirzabekov T., Choe H.;
RT "The role of post-translational modifications of the CXCR4 amino terminus
RT in stromal-derived factor 1 alpha association and HIV-1 entry.";
RL J. Biol. Chem. 277:29484-29489(2002).
RN [35]
RP UBIQUITINATION BY ITCH, AND SUBCELLULAR LOCATION.
RX PubMed=14602072; DOI=10.1016/s1534-5807(03)00321-6;
RA Marchese A., Raiborg C., Santini F., Keen J.H., Stenmark H., Benovic J.L.;
RT "The E3 ubiquitin ligase AIP4 mediates ubiquitination and sorting of the G
RT protein-coupled receptor CXCR4.";
RL Dev. Cell 5:709-722(2003).
RN [36]
RP INVOLVEMENT IN WHIMS1, AND VARIANTS WHIMS1 334-ARG--SER-352 DEL AND
RP 343-GLU--SER-352 DEL.
RX PubMed=12692554; DOI=10.1038/ng1149;
RA Hernandez P.A., Gorlin R.J., Lukens J.N., Taniuchi S., Bohinjec J.,
RA Francois F., Klotman M.E., Diaz G.A.;
RT "Mutations in the chemokine receptor gene CXCR4 are associated with WHIM
RT syndrome, a combined immunodeficiency disease.";
RL Nat. Genet. 34:70-74(2003).
RN [37]
RP INVOLVEMENT IN WHIMS1, AND VARIANT WHIMS1 338-SER--SER-352 DEL.
RX PubMed=15536153; DOI=10.1182/blood-2004-06-2289;
RA Balabanian K., Lagane B., Pablos J.L., Laurent L., Planchenault T.,
RA Verola O., Lebbe C., Kerob D., Dupuy A., Hermine O., Nicolas J.F.,
RA Latger-Cannard V., Bensoussan D., Bordigoni P., Baleux F., Le Deist F.,
RA Virelizier J.L., Arenzana-Seisdedos F., Bachelerie F.;
RT "WHIM syndromes with different genetic anomalies are accounted for by
RT impaired CXCR4 desensitization to CXCL12.";
RL Blood 105:2449-2457(2005).
RN [38]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [39]
RP INTERACTION WITH CD164.
RX PubMed=17077324; DOI=10.1182/blood-2006-05-023028;
RA Forde S., Tye B.J., Newey S.E., Roubelakis M., Smythe J., McGuckin C.P.,
RA Pettengell R., Watt S.M.;
RT "Endolyn (CD164) modulates the CXCL12-mediated migration of umbilical cord
RT blood CD133+ cells.";
RL Blood 109:1825-1833(2007).
RN [40]
RP FUNCTION, AND MUTAGENESIS OF ASN-119; ASP-133; ARG-134 AND TYR-135.
RX PubMed=17197449; DOI=10.1074/jbc.c600270200;
RA Berchiche Y.A., Chow K.Y., Lagane B., Leduc M., Percherancier Y., Fujii N.,
RA Tamamura H., Bachelerie F., Heveker N.;
RT "Direct assessment of CXCR4 mutant conformations reveals complex link
RT between receptor structure and G(alpha)(i) activation.";
RL J. Biol. Chem. 282:5111-5115(2007).
RN [41]
RP SULFATION AT TYR-7; TYR-12 AND TYR-21, AND INTERACTION WITH CXCL12.
RX PubMed=18834145; DOI=10.1021/bi800965m;
RA Seibert C., Veldkamp C.T., Peterson F.C., Chait B.T., Volkman B.F.,
RA Sakmar T.P.;
RT "Sequential tyrosine sulfation of CXCR4 by tyrosylprotein
RT sulfotransferases.";
RL Biochemistry 47:11251-11262(2008).
RN [42]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient
RT phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [43]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-319 AND SER-348, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [44]
RP INTERACTION WITH ITCH, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-324 AND
RP SER-325, AND MUTAGENESIS OF SER-324; SER-325 AND SER-330.
RX PubMed=19116316; DOI=10.1091/mbc.e08-03-0308;
RA Bhandari D., Robia S.L., Marchese A.;
RT "The E3 ubiquitin ligase atrophin interacting protein 4 binds directly to
RT the chemokine receptor CXCR4 via a novel WW domain-mediated interaction.";
RL Mol. Biol. Cell 20:1324-1339(2009).
RN [45]
RP INTERACTION WITH STAPHYLOCOCCUS AUREUS SUPERANTIGEN-LIKE PROTEIN 10
RP (MICROBIAL INFECTION).
RX PubMed=19308288; DOI=10.1593/neo.81508;
RA Walenkamp A.M., Boer I.G., Bestebroer J., Rozeveld D., Timmer-Bosscha H.,
RA Hemrika W., van Strijp J.A., de Haas C.J.;
RT "Staphylococcal superantigen-like 10 inhibits CXCL12-induced human tumor
RT cell migration.";
RL Neoplasia 11:333-344(2009).
RN [46]
RP PHOSPHORYLATION AT SER-321; SER-324; SER-325; SER-330; SER-339 AND SER-351,
RP INTERACTION WITH ARRB2 AND ARR3, FUNCTION, AND IDENTIFICATION BY MASS
RP SPECTROMETRY.
RX PubMed=20048153; DOI=10.1074/jbc.m109.091173;
RA Busillo J.M., Armando S., Sengupta R., Meucci O., Bouvier M., Benovic J.L.;
RT "Site-specific phosphorylation of CXCR4 is dynamically regulated by
RT multiple kinases and results in differential modulation of CXCR4
RT signaling.";
RL J. Biol. Chem. 285:7805-7817(2010).
RN [47]
RP FUNCTION, AND INTERACTION WITH UBIQUITIN.
RX PubMed=20228059; DOI=10.1074/jbc.m110.103408;
RA Saini V., Marchese A., Majetschak M.;
RT "CXC chemokine receptor 4 is a cell surface receptor for extracellular
RT ubiquitin.";
RL J. Biol. Chem. 285:15566-15576(2010).
RN [48]
RP INTERACTION WITH DBN1, AND SUBCELLULAR LOCATION.
RX PubMed=20215400; DOI=10.1242/jcs.064238;
RA Perez-Martinez M., Gordon-Alonso M., Cabrero J.R., Barrero-Villar M.,
RA Rey M., Mittelbrunn M., Lamana A., Morlino G., Calabia C., Yamazaki H.,
RA Shirao T., Vazquez J., Gonzalez-Amaro R., Veiga E., Sanchez-Madrid F.;
RT "F-actin-binding protein drebrin regulates CXCR4 recruitment to the immune
RT synapse.";
RL J. Cell Sci. 123:1160-1170(2010).
RN [49]
RP FUNCTION, AND INTERACTION WITH UBIQUITIN.
RX PubMed=20505072; DOI=10.1091/mbc.e10-02-0169;
RA Malik R., Marchese A.;
RT "Arrestin-2 interacts with the endosomal sorting complex required for
RT transport machinery to modulate endosomal sorting of CXCR4.";
RL Mol. Biol. Cell 21:2529-2541(2010).
RN [50]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [51]
RP SUBCELLULAR LOCATION.
RX PubMed=21540189; DOI=10.1074/jbc.m111.224071;
RA Cheng S.B., Quinn J.A., Graeber C.T., Filardo E.J.;
RT "Down-modulation of the G-protein-coupled estrogen receptor, GPER, from the
RT cell surface occurs via a trans-Golgi-proteasome pathway.";
RL J. Biol. Chem. 286:22441-22455(2011).
RN [52]
RP INDUCTION (MICROBIAL INFECTION), AND INTERACTION WITH HHV-5 PROTEIN UL78.
RX PubMed=22496149; DOI=10.1182/blood-2011-08-372516;
RA Tadagaki K., Tudor D., Gbahou F., Tschische P., Waldhoer M., Bomsel M.,
RA Jockers R., Kamal M.;
RT "Human cytomegalovirus-encoded UL33 and UL78 heteromerize with host CCR5
RT and CXCR4 impairing their HIV coreceptor activity.";
RL Blood 119:4908-4918(2012).
RN [53]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-321; SER-324 AND SER-325, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [54]
RP INVOLVEMENT IN WALDENSTROEM MACROGLOBULINEMIA, AND VARIANT 338-SER--SER-352
RP DEL.
RX PubMed=24366360; DOI=10.1182/blood-2013-09-525808;
RA Hunter Z.R., Xu L., Yang G., Zhou Y., Liu X., Cao Y., Manning R.J.,
RA Tripsas C., Patterson C.J., Sheehy P., Treon S.P.;
RT "The genomic landscape of Waldenstrom macroglobulinemia is characterized by
RT highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic
RT deletions associated with B-cell lymphomagenesis.";
RL Blood 123:1637-1646(2014).
RN [55]
RP INVOLVEMENT IN WALDENSTROEM MACROGLOBULINEMIA, AND VARIANTS
RP 333-LYS--SER-352 DEL; 334-ARG--SER-352 DEL AND 338-SER--SER-352 DEL.
RX PubMed=24553177; DOI=10.1182/blood-2014-01-550905;
RA Treon S.P., Cao Y., Xu L., Yang G., Liu X., Hunter Z.R.;
RT "Somatic mutations in MYD88 and CXCR4 are determinants of clinical
RT presentation and overall survival in Waldenstrom macroglobulinemia.";
RL Blood 123:2791-2796(2014).
RN [56]
RP FUNCTION, AND CHARACTERIZATION OF VARIANT 338-SER--SER-352 DEL.
RX PubMed=24912431; DOI=10.1038/leu.2014.187;
RA Cao Y., Hunter Z.R., Liu X., Xu L., Yang G., Chen J., Patterson C.J.,
RA Tsakmaklis N., Kanan S., Rodig S., Castillo J.J., Treon S.P.;
RT "The WHIM-like CXCR4(S338X) somatic mutation activates AKT and ERK, and
RT promotes resistance to ibrutinib and other agents used in the treatment of
RT Waldenstrom's Macroglobulinemia.";
RL Leukemia 29:169-176(2015).
RN [57]
RP FUNCTION, UBIQUITINATION, AND MUTAGENESIS OF LYS-331.
RX PubMed=28978524; DOI=10.1152/ajpcell.00193.2017;
RA Lear T., Dunn S.R., McKelvey A.C., Mir A., Evankovich J., Chen B.B.,
RA Liu Y.;
RT "RING finger protein 113A regulates C-X-C chemokine receptor type 4
RT stability and signaling.";
RL Am. J. Physiol. 313:C584-C592(2017).
RN [58]
RP STRUCTURE BY NMR OF 1-38, SULFATION AT TYR-21, IDENTIFICATION BY MASS
RP SPECTROMETRY, AND INTERACTION WITH CXCL12.
RX PubMed=16725153; DOI=10.1016/j.jmb.2006.04.052;
RA Veldkamp C.T., Seibert C., Peterson F.C., Sakmar T.P., Volkman B.F.;
RT "Recognition of a CXCR4 sulfotyrosine by the chemokine stromal cell-derived
RT factor-1alpha (SDF-1alpha/CXCL12).";
RL J. Mol. Biol. 359:1400-1409(2006).
RN [59]
RP STRUCTURE BY NMR OF 1-38 OF SULFATED MUTANT ALA-28 IN COMPLEX WITH CXCL12.
RX PubMed=18799424; DOI=10.1126/scisignal.1160755;
RA Veldkamp C.T., Seibert C., Peterson F.C., De la Cruz N.B.,
RA Haugner J.C. III, Basnet H., Sakmar T.P., Volkman B.F.;
RT "Structural basis of CXCR4 sulfotyrosine recognition by the chemokine SDF-
RT 1/CXCL12.";
RL Sci. Signal. 1:RA4-RA4(2008).
RN [60] {ECO:0007744|PDB:3ODU, ECO:0007744|PDB:3OE0, ECO:0007744|PDB:3OE6, ECO:0007744|PDB:3OE8, ECO:0007744|PDB:3OE9}
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 2-325 OF MUTANTS LEU-125 AND
RP THR-240 IN COMPLEX WITH ANTAGONISTS CVX15 AND IT1T, SUBCELLULAR LOCATION,
RP TOPOLOGY, HOMODIMERIZATION, AND DISULFIDE BONDS.
RX PubMed=20929726; DOI=10.1126/science.1194396;
RA Wu B., Chien E.Y., Mol C.D., Fenalti G., Liu W., Katritch V., Abagyan R.,
RA Brooun A., Wells P., Bi F.C., Hamel D.J., Kuhn P., Handel T.M.,
RA Cherezov V., Stevens R.C.;
RT "Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic
RT peptide antagonists.";
RL Science 330:1066-1071(2010).
RN [61]
RP X-RAY CRYSTALLOGRAPHY (3.10 ANGSTROMS) OF 2-319 IN COMPLEX WITH HHV-8 VIRUS
RP ORF K4 PROTEIN, AND INTERACTION WITH HHV-8 VIRUS ORF K4 PROTEIN.
RX PubMed=25612609; DOI=10.1126/science.1261064;
RA Qin L., Kufareva I., Holden L.G., Wang C., Zheng Y., Zhao C., Fenalti G.,
RA Wu H., Han G.W., Cherezov V., Abagyan R., Stevens R.C., Handel T.M.;
RT "Structural biology. Crystal structure of the chemokine receptor CXCR4 in
RT complex with a viral chemokine.";
RL Science 347:1117-1122(2015).
CC -!- FUNCTION: Receptor for the C-X-C chemokine CXCL12/SDF-1 that transduces
CC a signal by increasing intracellular calcium ion levels and enhancing
CC MAPK1/MAPK3 activation (PubMed:10452968, PubMed:28978524,
CC PubMed:18799424, PubMed:24912431). Involved in the AKT signaling
CC cascade (PubMed:24912431). Plays a role in regulation of cell
CC migration, e.g. during wound healing (PubMed:28978524). Acts as a
CC receptor for extracellular ubiquitin; leading to enhanced intracellular
CC calcium ions and reduced cellular cAMP levels (PubMed:20228059). Binds
CC bacterial lipopolysaccharide (LPS) et mediates LPS-induced inflammatory
CC response, including TNF secretion by monocytes (PubMed:11276205).
CC Involved in hematopoiesis and in cardiac ventricular septum formation.
CC Also plays an essential role in vascularization of the gastrointestinal
CC tract, probably by regulating vascular branching and/or remodeling
CC processes in endothelial cells. Involved in cerebellar development. In
CC the CNS, could mediate hippocampal-neuron survival (By similarity).
CC {ECO:0000250|UniProtKB:P70658, ECO:0000269|PubMed:10074102,
CC ECO:0000269|PubMed:10452968, ECO:0000269|PubMed:10644702,
CC ECO:0000269|PubMed:10825158, ECO:0000269|PubMed:11276205,
CC ECO:0000269|PubMed:17197449, ECO:0000269|PubMed:18799424,
CC ECO:0000269|PubMed:20048153, ECO:0000269|PubMed:20228059,
CC ECO:0000269|PubMed:20505072, ECO:0000269|PubMed:24912431,
CC ECO:0000269|PubMed:28978524, ECO:0000269|PubMed:8752280,
CC ECO:0000269|PubMed:8752281}.
CC -!- FUNCTION: (Microbial infection) Acts as a coreceptor (CD4 being the
CC primary receptor) for human immunodeficiency virus-1/HIV-1 X4 isolates
CC and as a primary receptor for some HIV-2 isolates. Promotes Env-
CC mediated fusion of the virus (PubMed:8849450, PubMed:8929542,
CC PubMed:9427609, PubMed:10074122, PubMed:10756055).
CC {ECO:0000269|PubMed:10074122, ECO:0000269|PubMed:10756055,
CC ECO:0000269|PubMed:8849450, ECO:0000269|PubMed:8929542,
CC ECO:0000269|PubMed:9427609}.
CC -!- SUBUNIT: Monomer. Can form homodimers (PubMed:20929726). Interacts with
CC CD164 (PubMed:17077324). Interacts with ARRB2; the interaction is
CC dependent on the C-terminal phosphorylation of CXCR4 and allows
CC activation of MAPK1 and MAPK3. Interacts with ARR3; the interaction is
CC dependent on the C-terminal phosphorylation of CXCR4 and modulates
CC calcium mobilization (PubMed:20048153). Interacts with RNF113A; the
CC interaction, enhanced by CXCL12, promotes CXCR4 ubiquitination and
CC subsequent degradation (PubMed:28978524). Interacts (via the
CC cytoplasmic C-terminal) with ITCH (via the WW domains I and II); the
CC interaction, enhanced by CXCL12, promotes CXCR4 ubiquitination and
CC leads to its degradation. Interacts with extracellular ubiquitin.
CC Interacts with DBN1; this interaction is enhanced by antigenic
CC stimulation. Following LPS binding, may form a complex with GDF5,
CC HSP90AA1 and HSPA8. {ECO:0000269|PubMed:10644702,
CC ECO:0000269|PubMed:10825158, ECO:0000269|PubMed:11276205,
CC ECO:0000269|PubMed:12034737, ECO:0000269|PubMed:16725153,
CC ECO:0000269|PubMed:17077324, ECO:0000269|PubMed:18799424,
CC ECO:0000269|PubMed:18834145, ECO:0000269|PubMed:19116316,
CC ECO:0000269|PubMed:20048153, ECO:0000269|PubMed:20215400,
CC ECO:0000269|PubMed:20228059, ECO:0000269|PubMed:20505072,
CC ECO:0000269|PubMed:20929726, ECO:0000269|PubMed:28978524}.
CC -!- SUBUNIT: (Microbial infection) Interacts with HIV-1 surface protein
CC gp120 and Tat. {ECO:0000269|PubMed:10074122,
CC ECO:0000269|PubMed:10756055, ECO:0000269|PubMed:11027346,
CC ECO:0000269|PubMed:25612609}.
CC -!- SUBUNIT: (Microbial infection) Interacts with HHV-8 protein ORF K4
CC (PubMed:25612609). {ECO:0000269|PubMed:9427609}.
CC -!- SUBUNIT: (Microbial infection) May interact with human
CC cytomegalovirus/HHV-5 protein UL78. {ECO:0000269|PubMed:22496149}.
CC -!- SUBUNIT: (Microbial infection) Interacts with Staphylococcus aureus
CC protein SSL10. {ECO:0000269|PubMed:19308288}.
CC -!- INTERACTION:
CC P61073; P25106: ACKR3; NbExp=18; IntAct=EBI-489411, EBI-1965291;
CC P61073; P51681: CCR5; NbExp=4; IntAct=EBI-489411, EBI-489374;
CC P61073; Q04900: CD164; NbExp=2; IntAct=EBI-489411, EBI-2115896;
CC P61073; P04233: CD74; NbExp=4; IntAct=EBI-489411, EBI-2622890;
CC P61073; P49682: CXCR3; NbExp=5; IntAct=EBI-489411, EBI-12836456;
CC P61073; P32302: CXCR5; NbExp=3; IntAct=EBI-489411, EBI-2835269;
CC P61073; Q16643: DBN1; NbExp=5; IntAct=EBI-489411, EBI-351394;
CC P61073; Q96J02-2: ITCH; NbExp=3; IntAct=EBI-489411, EBI-6672198;
CC P61073; P35579: MYH9; NbExp=5; IntAct=EBI-489411, EBI-350338;
CC P61073; O60603: TLR2; NbExp=3; IntAct=EBI-489411, EBI-973722;
CC P61073; Q07266-1: Dbn1; Xeno; NbExp=3; IntAct=EBI-489411, EBI-8786792;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:10452968,
CC ECO:0000305|PubMed:20929726}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:20929726}. Cell junction. Early endosome. Late
CC endosome. Lysosome. Note=In unstimulated cells, diffuse pattern on
CC plasma membrane. On agonist stimulation, colocalizes with ITCH at the
CC plasma membrane where it becomes ubiquitinated. In the presence of
CC antigen, distributes to the immunological synapse forming at the T-
CC cell-APC contact area, where it localizes at the peripheral and distal
CC supramolecular activation cluster (SMAC).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Comment=Additional isoforms seem to exist.;
CC Name=1;
CC IsoId=P61073-1, P30991-1;
CC Sequence=Displayed;
CC Name=2; Synonyms=CXCR4-LO;
CC IsoId=P61073-2, P30991-2;
CC Sequence=VSP_001890;
CC -!- TISSUE SPECIFICITY: Expressed in numerous tissues, such as peripheral
CC blood leukocytes, spleen, thymus, spinal cord, heart, placenta, lung,
CC liver, skeletal muscle, kidney, pancreas, cerebellum, cerebral cortex
CC and medulla (in microglia as well as in astrocytes), brain
CC microvascular, coronary artery and umbilical cord endothelial cells.
CC Isoform 1 is predominant in all tissues tested.
CC {ECO:0000269|PubMed:11276205}.
CC -!- INDUCTION: (Microbial infection) May be down-regulated by Human
CC cytomegalovirus/HHV-5. {ECO:0000269|PubMed:22496149}.
CC -!- INDUCTION: (Microbial infection) May be down-regulated by HIV-1 tat.
CC {ECO:0000269|PubMed:11027346}.
CC -!- DOMAIN: The amino-terminus is critical for ligand binding. Residues in
CC all four extracellular regions contribute to HIV-1 coreceptor activity.
CC {ECO:0000269|PubMed:10074122}.
CC -!- PTM: Phosphorylated on agonist stimulation. Rapidly phosphorylated on
CC serine and threonine residues in the C-terminal. Phosphorylation at
CC Ser-324 and Ser-325 leads to recruitment of ITCH, ubiquitination and
CC protein degradation. {ECO:0000269|PubMed:14602072,
CC ECO:0000269|PubMed:19116316, ECO:0000269|PubMed:20048153}.
CC -!- PTM: Ubiquitinated after ligand binding, leading to its degradation
CC (PubMed:28978524). Ubiquitinated by ITCH at the cell membrane on
CC agonist stimulation. The ubiquitin-dependent mechanism, endosomal
CC sorting complex required for transport (ESCRT), then targets CXCR4 for
CC lysosomal degradation. This process is dependent also on prior
CC Ser-/Thr-phosphorylation in the C-terminal of CXCR4. Also binding of
CC ARRB1 to STAM negatively regulates CXCR4 sorting to lysosomes though
CC modulating ubiquitination of SFR5S. {ECO:0000269|PubMed:14602072,
CC ECO:0000269|PubMed:28978524}.
CC -!- PTM: Sulfation on Tyr-21 is required for efficient binding of
CC CXCL12/SDF-1alpha and promotes its dimerization. Tyr-7 and Tyr-12 are
CC sulfated in a sequential manner after Tyr-21 is almost fully sulfated,
CC with the binding affinity for CXCL12/SDF-1alpha increasing with the
CC number of sulfotyrosines present. Sulfotyrosines Tyr-7 and Tyr-12
CC occupy clefts on opposing CXCL12 subunits, thus bridging the CXCL12
CC dimer interface and promoting CXCL12 dimerization.
CC {ECO:0000269|PubMed:10089882, ECO:0000269|PubMed:12034737,
CC ECO:0000269|PubMed:16725153, ECO:0000269|PubMed:18834145}.
CC -!- PTM: O- and N-glycosylated. Asn-11 is the principal site of N-
CC glycosylation. There appears to be very little or no glycosylation on
CC Asn-176. N-glycosylation masks coreceptor function in both X4 and R5
CC laboratory-adapted and primary HIV-1 strains through inhibiting
CC interaction with their Env glycoproteins. The O-glycosylation
CC chondroitin sulfate attachment does not affect interaction with
CC CXCL12/SDF-1alpha nor its coreceptor activity.
CC {ECO:0000269|PubMed:10756055, ECO:0000269|PubMed:12034737}.
CC -!- DISEASE: WHIM syndrome 1 (WHIMS1) [MIM:193670]: An autosomal dominant
CC immunologic disease characterized by neutropenia, hypogammaglobulinemia
CC and extensive human papillomavirus (HPV) infection. Despite the
CC peripheral neutropenia, bone marrow aspirates from affected individuals
CC contain abundant mature myeloid cells, a condition termed
CC myelokathexis. {ECO:0000269|PubMed:12692554,
CC ECO:0000269|PubMed:15536153}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Note=CXCR4 mutations play a role in the pathogenesis of
CC Waldenstroem macroglobulinemia (WM) and influence disease presentation
CC and outcome, as well as response to therapy. WM is a B-cell lymphoma
CC characterized by accumulation of malignant lymphoplasmacytic cells in
CC the bone marrow, lymph nodes and spleen, and hypersecretion of
CC monoclonal immunoglobulin M (IgM). Excess IgM production results in
CC serum hyperviscosity, tissue infiltration, and autoimmune-related
CC pathology. {ECO:0000269|PubMed:24366360, ECO:0000269|PubMed:24553177}.
CC -!- MISCELLANEOUS: Plerixafor (AMD3100), an antagonist of CXCR4 activity,
CC blocks HIV-1 entry, interaction with CXCL12 and subsequent CXCR4
CC signaling.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
CC {ECO:0000255|PROSITE-ProRule:PRU00521}.
CC -!- CAUTION: Was originally thought to be a receptor for neuropeptide Y
CC type 3 (NPY3R) (NPY3-R) (PubMed:8329116 and PubMed:8234909). Later
CC reports showed that it acts as a receptor for the C-X-C chemokine
CC CXCL12/SDF-1 (PubMed:9427609, PubMed:10825158, PubMed:12034737).
CC {ECO:0000269|PubMed:10825158, ECO:0000269|PubMed:12034737,
CC ECO:0000269|PubMed:9427609, ECO:0000305|PubMed:8234909,
CC ECO:0000305|PubMed:8329116}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA12166.1; Type=Miscellaneous discrepancy; Note=Intron retention.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=CXCR4base; Note=CXCR4 mutation db;
CC URL="http://structure.bmc.lu.se/idbase/CXCR4base/";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=CXC chemokine receptors entry;
CC URL="https://en.wikipedia.org/wiki/CXC_chemokine_receptors";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=CXCR4 entry;
CC URL="https://en.wikipedia.org/wiki/CXCR4";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/cxcr4/";
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DR EMBL; L01639; AAA16594.1; -; mRNA.
DR EMBL; M99293; AAA16617.1; -; mRNA.
DR EMBL; X71635; CAA50641.1; -; mRNA.
DR EMBL; L06797; AAA03209.1; -; mRNA.
DR EMBL; D10924; BAA01722.1; -; mRNA.
DR EMBL; AF005058; AAB93982.1; -; Genomic_DNA.
DR EMBL; AF052572; AAC34581.1; -; Genomic_DNA.
DR EMBL; AJ224869; CAA12166.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AF025375; AAB81970.1; -; mRNA.
DR EMBL; Y14739; CAA75034.1; -; Genomic_DNA.
DR EMBL; AF147204; AAF00130.1; -; mRNA.
DR EMBL; AF348491; AAK29630.1; -; mRNA.
DR EMBL; AK312244; BAG35177.1; -; mRNA.
DR EMBL; AY242129; AAO92296.1; -; mRNA.
DR EMBL; BT006660; AAP35306.1; -; mRNA.
DR EMBL; AY728138; AAU05775.1; -; Genomic_DNA.
DR EMBL; AC068492; AAY24044.1; -; Genomic_DNA.
DR EMBL; CH471058; EAX11616.1; -; Genomic_DNA.
DR EMBL; BC020968; AAH20968.1; -; mRNA.
DR CCDS; CCDS33295.1; -. [P61073-2]
DR CCDS; CCDS46420.1; -.
DR PIR; A45747; A45747.
DR RefSeq; NP_001008540.1; NM_001008540.2. [P61073-2]
DR RefSeq; NP_001334985.1; NM_001348056.1.
DR RefSeq; NP_001334988.1; NM_001348059.1.
DR RefSeq; NP_001334989.1; NM_001348060.1.
DR RefSeq; NP_003458.1; NM_003467.2. [P61073-1]
DR PDB; 2K03; NMR; -; B/D=1-38.
DR PDB; 2K04; NMR; -; B/D=1-38.
DR PDB; 2K05; NMR; -; B/D=1-38.
DR PDB; 2N55; NMR; -; B=1-38.
DR PDB; 3ODU; X-ray; 2.50 A; A/B=2-319.
DR PDB; 3OE0; X-ray; 2.90 A; A=2-319.
DR PDB; 3OE6; X-ray; 3.20 A; A=2-325.
DR PDB; 3OE8; X-ray; 3.10 A; A/B/C=2-319.
DR PDB; 3OE9; X-ray; 3.10 A; A/B=2-319.
DR PDB; 4RWS; X-ray; 3.10 A; A=2-228, A=231-319.
DR PDBsum; 2K03; -.
DR PDBsum; 2K04; -.
DR PDBsum; 2K05; -.
DR PDBsum; 2N55; -.
DR PDBsum; 3ODU; -.
DR PDBsum; 3OE0; -.
DR PDBsum; 3OE6; -.
DR PDBsum; 3OE8; -.
DR PDBsum; 3OE9; -.
DR PDBsum; 4RWS; -.
DR AlphaFoldDB; P61073; -.
DR BMRB; P61073; -.
DR SMR; P61073; -.
DR BioGRID; 113607; 243.
DR CORUM; P61073; -.
DR DIP; DIP-34773N; -.
DR DIP; DIP-46290N; -.
DR IntAct; P61073; 41.
DR MINT; P61073; -.
DR STRING; 9606.ENSP00000386884; -.
DR BindingDB; P61073; -.
DR ChEMBL; CHEMBL2107; -.
DR DrugBank; DB05501; AMD-070.
DR DrugBank; DB00452; Framycetin.
DR DrugBank; DB12698; Ibalizumab.
DR DrugBank; DB06809; Plerixafor.
DR DrugCentral; P61073; -.
DR GuidetoPHARMACOLOGY; 71; -.
DR TCDB; 9.A.14.13.17; the g-protein-coupled receptor (gpcr) family.
DR GlyGen; P61073; 3 sites.
DR iPTMnet; P61073; -.
DR PhosphoSitePlus; P61073; -.
DR SwissPalm; P61073; -.
DR BioMuta; CXCR4; -.
DR DMDM; 46577576; -.
DR EPD; P61073; -.
DR jPOST; P61073; -.
DR MassIVE; P61073; -.
DR MaxQB; P61073; -.
DR PaxDb; P61073; -.
DR PeptideAtlas; P61073; -.
DR PRIDE; P61073; -.
DR ProteomicsDB; 57256; -.
DR ProteomicsDB; 57257; -. [P61073-2]
DR ABCD; P61073; 38 sequenced antibodies.
DR Antibodypedia; 4421; 1734 antibodies from 53 providers.
DR DNASU; 7852; -.
DR Ensembl; ENST00000241393.4; ENSP00000241393.3; ENSG00000121966.7. [P61073-1]
DR Ensembl; ENST00000409817.1; ENSP00000386884.1; ENSG00000121966.7. [P61073-2]
DR GeneID; 7852; -.
DR KEGG; hsa:7852; -.
DR MANE-Select; ENST00000241393.4; ENSP00000241393.3; NM_003467.3; NP_003458.1.
DR UCSC; uc002tuy.3; human.
DR CTD; 7852; -.
DR DisGeNET; 7852; -.
DR GeneCards; CXCR4; -.
DR HGNC; HGNC:2561; CXCR4.
DR HPA; ENSG00000121966; Tissue enhanced (bone marrow, lymphoid tissue).
DR MalaCards; CXCR4; -.
DR MIM; 162643; gene.
DR MIM; 193670; phenotype.
DR neXtProt; NX_P61073; -.
DR OpenTargets; ENSG00000121966; -.
DR Orphanet; 51636; WHIM syndrome.
DR PharmGKB; PA27058; -.
DR VEuPathDB; HostDB:ENSG00000121966; -.
DR eggNOG; KOG3656; Eukaryota.
DR GeneTree; ENSGT01050000244848; -.
DR HOGENOM; CLU_009579_8_3_1; -.
DR InParanoid; P61073; -.
DR OMA; TIVHKWI; -.
DR OrthoDB; 773026at2759; -.
DR PhylomeDB; P61073; -.
DR TreeFam; TF330966; -.
DR PathwayCommons; P61073; -.
DR Reactome; R-HSA-173107; Binding and entry of HIV virion.
DR Reactome; R-HSA-376176; Signaling by ROBO receptors.
DR Reactome; R-HSA-380108; Chemokine receptors bind chemokines.
DR Reactome; R-HSA-418594; G alpha (i) signalling events.
DR SignaLink; P61073; -.
DR SIGNOR; P61073; -.
DR BioGRID-ORCS; 7852; 8 hits in 1074 CRISPR screens.
DR ChiTaRS; CXCR4; human.
DR EvolutionaryTrace; P61073; -.
DR GeneWiki; CXCR4; -.
DR GenomeRNAi; 7852; -.
DR Pharos; P61073; Tclin.
DR PRO; PR:P61073; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; P61073; protein.
DR Bgee; ENSG00000121966; Expressed in bone marrow and 197 other tissues.
DR Genevisible; P61073; HS.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-SubCell.
DR GO; GO:0031252; C:cell leading edge; IDA:UniProtKB.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; TAS:ProtInc.
DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:UniProtKB.
DR GO; GO:0005769; C:early endosome; IDA:UniProtKB.
DR GO; GO:0009897; C:external side of plasma membrane; IBA:GO_Central.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005770; C:late endosome; IDA:UniProtKB.
DR GO; GO:0005764; C:lysosome; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; IDA:ARUK-UCL.
DR GO; GO:0003779; F:actin binding; IDA:UniProtKB.
DR GO; GO:0019957; F:C-C chemokine binding; IPI:CAFA.
DR GO; GO:0016493; F:C-C chemokine receptor activity; IBA:GO_Central.
DR GO; GO:0016494; F:C-X-C chemokine receptor activity; NAS:UniProtKB.
DR GO; GO:0038147; F:C-X-C motif chemokine 12 receptor activity; IDA:UniProtKB.
DR GO; GO:0015026; F:coreceptor activity; TAS:ProtInc.
DR GO; GO:0004930; F:G protein-coupled receptor activity; TAS:ProtInc.
DR GO; GO:0032027; F:myosin light chain binding; IDA:UniProtKB.
DR GO; GO:0036094; F:small molecule binding; IEA:Ensembl.
DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
DR GO; GO:0001618; F:virus receptor activity; IEA:UniProtKB-KW.
DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc.
DR GO; GO:0007420; P:brain development; IBA:GO_Central.
DR GO; GO:0019722; P:calcium-mediated signaling; IMP:MGI.
DR GO; GO:0060048; P:cardiac muscle contraction; IEA:Ensembl.
DR GO; GO:0060326; P:cell chemotaxis; IBA:GO_Central.
DR GO; GO:0071345; P:cellular response to cytokine stimulus; IDA:UniProtKB.
DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0038160; P:CXCL12-activated CXCR4 signaling pathway; IDA:UniProtKB.
DR GO; GO:0002407; P:dendritic cell chemotaxis; TAS:BHF-UCL.
DR GO; GO:0050966; P:detection of mechanical stimulus involved in sensory perception of pain; IEA:Ensembl.
DR GO; GO:0050965; P:detection of temperature stimulus involved in sensory perception of pain; IEA:Ensembl.
DR GO; GO:0045446; P:endothelial cell differentiation; IEA:Ensembl.
DR GO; GO:0061154; P:endothelial tube morphogenesis; IEA:Ensembl.
DR GO; GO:0002064; P:epithelial cell development; IEA:Ensembl.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0006955; P:immune response; IBA:GO_Central.
DR GO; GO:0006954; P:inflammatory response; TAS:ProtInc.
DR GO; GO:0043217; P:myelin maintenance; ISS:BHF-UCL.
DR GO; GO:0022008; P:neurogenesis; IBA:GO_Central.
DR GO; GO:0001764; P:neuron migration; IEA:Ensembl.
DR GO; GO:0008038; P:neuron recognition; IEA:Ensembl.
DR GO; GO:0050921; P:positive regulation of chemotaxis; IEA:Ensembl.
DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR GO; GO:0007204; P:positive regulation of cytosolic calcium ion concentration; IBA:GO_Central.
DR GO; GO:1903861; P:positive regulation of dendrite extension; IEA:Ensembl.
DR GO; GO:2000448; P:positive regulation of macrophage migration inhibitory factor signaling pathway; IMP:ARUK-UCL.
DR GO; GO:1905322; P:positive regulation of mesenchymal stem cell migration; IEA:Ensembl.
DR GO; GO:0048714; P:positive regulation of oligodendrocyte differentiation; ISS:BHF-UCL.
DR GO; GO:0035470; P:positive regulation of vascular wound healing; IEA:Ensembl.
DR GO; GO:0051924; P:regulation of calcium ion transport; IEA:Ensembl.
DR GO; GO:0030155; P:regulation of cell adhesion; IDA:UniProtKB.
DR GO; GO:0050920; P:regulation of chemotaxis; IMP:UniProtKB.
DR GO; GO:0043067; P:regulation of programmed cell death; IEA:Ensembl.
DR GO; GO:0050792; P:regulation of viral process; IEA:Ensembl.
DR GO; GO:0014823; P:response to activity; IEA:Ensembl.
DR GO; GO:0001666; P:response to hypoxia; IEP:UniProtKB.
DR GO; GO:0043278; P:response to morphine; IEA:Ensembl.
DR GO; GO:1990478; P:response to ultrasound; IEA:Ensembl.
DR GO; GO:0009615; P:response to virus; TAS:ProtInc.
DR GO; GO:0022029; P:telencephalon cell migration; IEA:Ensembl.
DR DisProt; DP01249; -.
DR InterPro; IPR022726; Chemokine_CXCR4_N_dom.
DR InterPro; IPR000355; Chemokine_rcpt.
DR InterPro; IPR001277; CXCR4/ACKR2.
DR InterPro; IPR000276; GPCR_Rhodpsn.
DR InterPro; IPR017452; GPCR_Rhodpsn_7TM.
DR Pfam; PF00001; 7tm_1; 1.
DR Pfam; PF12109; CXCR4_N; 1.
DR PRINTS; PR00657; CCCHEMOKINER.
DR PRINTS; PR00645; CXCCHMKINER4.
DR PRINTS; PR00237; GPCRRHODOPSN.
DR PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1.
DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell junction; Cell membrane;
KW Disease variant; Disulfide bond; Endosome; G-protein coupled receptor;
KW Glycoprotein; Host cell receptor for virus entry; Host-virus interaction;
KW Isopeptide bond; Lysosome; Membrane; Phosphoprotein; Proteoglycan;
KW Receptor; Reference proteome; Sulfation; Transducer; Transmembrane;
KW Transmembrane helix; Ubl conjugation.
FT CHAIN 1..352
FT /note="C-X-C chemokine receptor type 4"
FT /id="PRO_0000069352"
FT TOPO_DOM 1..38
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:20929726"
FT TRANSMEM 39..63
FT /note="Helical; Name=1"
FT /evidence="ECO:0000269|PubMed:20929726"
FT TOPO_DOM 64..77
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:20929726"
FT TRANSMEM 78..99
FT /note="Helical; Name=2"
FT /evidence="ECO:0000269|PubMed:20929726"
FT TOPO_DOM 100..110
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:20929726"
FT TRANSMEM 111..130
FT /note="Helical; Name=3"
FT /evidence="ECO:0000269|PubMed:20929726"
FT TOPO_DOM 131..154
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:20929726"
FT TRANSMEM 155..174
FT /note="Helical; Name=4"
FT /evidence="ECO:0000269|PubMed:20929726"
FT TOPO_DOM 175..195
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:20929726"
FT TRANSMEM 196..216
FT /note="Helical; Name=5"
FT /evidence="ECO:0000269|PubMed:20929726"
FT TOPO_DOM 217..241
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:20929726"
FT TRANSMEM 242..261
FT /note="Helical; Name=6"
FT /evidence="ECO:0000269|PubMed:20929726"
FT TOPO_DOM 262..282
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:20929726"
FT TRANSMEM 283..302
FT /note="Helical; Name=7"
FT /evidence="ECO:0000269|PubMed:20929726"
FT TOPO_DOM 303..352
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:20929726"
FT REGION 1..21
FT /note="Important for chemokine binding, signaling and HIV-1
FT coreceptor activity"
FT /evidence="ECO:0000269|PubMed:10825158"
FT REGION 94..97
FT /note="Chemokine binding"
FT /evidence="ECO:0000269|PubMed:20929726,
FT ECO:0000305|PubMed:10825158"
FT REGION 113..117
FT /note="Chemokine binding"
FT REGION 135..147
FT /note="Involved in dimerization; when bound to chemokine"
FT REGION 186..190
FT /note="Chemokine binding, important for signaling and HIV-1
FT coreceptor activity"
FT REGION 191..210
FT /note="Involved in dimerization"
FT REGION 266..268
FT /note="Involved in dimerization"
FT REGION 329..352
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 133..135
FT /note="Important for signaling"
FT COMPBIAS 335..352
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 171
FT /note="Chemokine binding"
FT SITE 288
FT /note="Chemokine binding"
FT /evidence="ECO:0000269|PubMed:20929726,
FT ECO:0000305|PubMed:10825158"
FT MOD_RES 7
FT /note="Sulfotyrosine; partial"
FT /evidence="ECO:0000269|PubMed:18834145"
FT MOD_RES 12
FT /note="Sulfotyrosine; partial"
FT /evidence="ECO:0000269|PubMed:18834145"
FT MOD_RES 21
FT /note="Sulfotyrosine"
FT /evidence="ECO:0000269|PubMed:12034737,
FT ECO:0000269|PubMed:16725153, ECO:0000269|PubMed:18834145"
FT MOD_RES 319
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 321
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:20048153,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 324
FT /note="Phosphoserine; by PKC and GRK6"
FT /evidence="ECO:0000269|PubMed:19116316,
FT ECO:0000269|PubMed:20048153, ECO:0007744|PubMed:23186163"
FT MOD_RES 325
FT /note="Phosphoserine; by PKC and GRK6"
FT /evidence="ECO:0000269|PubMed:19116316,
FT ECO:0000269|PubMed:20048153, ECO:0007744|PubMed:23186163"
FT MOD_RES 330
FT /note="Phosphoserine; by GRK6"
FT /evidence="ECO:0000269|PubMed:20048153"
FT MOD_RES 339
FT /note="Phosphoserine; by GRK6"
FT /evidence="ECO:0000269|PubMed:20048153"
FT MOD_RES 348
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 351
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:20048153"
FT CARBOHYD 11
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:10756055"
FT CARBOHYD 18
FT /note="O-linked (Xyl...) (chondroitin sulfate) serine"
FT /evidence="ECO:0000269|PubMed:12034737"
FT CARBOHYD 176
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 28..274
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00521,
FT ECO:0000269|PubMed:20929726, ECO:0007744|PDB:3ODU,
FT ECO:0007744|PDB:3OE0, ECO:0007744|PDB:3OE8,
FT ECO:0007744|PDB:3OE9, ECO:0007744|PDB:4RWS"
FT DISULFID 109..186
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00521,
FT ECO:0000269|PubMed:20929726, ECO:0007744|PDB:3ODU,
FT ECO:0007744|PDB:3OE0, ECO:0007744|PDB:3OE6,
FT ECO:0007744|PDB:3OE8, ECO:0007744|PDB:3OE9,
FT ECO:0007744|PDB:4RWS"
FT CROSSLNK 331
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000305|PubMed:28978524"
FT VAR_SEQ 1..5
FT /note="MEGIS -> MSIPLPLLQ (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:10452968"
FT /id="VSP_001890"
FT VARIANT 333..352
FT /note="Missing (found in patients with Waldenstroem
FT macroglobulinemia; somatic mutation)"
FT /evidence="ECO:0000269|PubMed:24553177"
FT /id="VAR_081112"
FT VARIANT 334..352
FT /note="Missing (in WHIMS1; also found in patients with
FT Waldenstroem macroglobulinemia; somatic mutation)"
FT /evidence="ECO:0000269|PubMed:12692554,
FT ECO:0000269|PubMed:24553177"
FT /id="VAR_081113"
FT VARIANT 338..352
FT /note="Missing (in WHIMS1; common somatic mutation in
FT patients with Waldenstroem macroglobulinemia; results in
FT decreased CXCL12-triggered receptor internalization;
FT enhanced AKT and MAPK signaling activation; confers
FT resistance to ibrutinib-triggered apoptosis)"
FT /evidence="ECO:0000269|PubMed:15536153,
FT ECO:0000269|PubMed:24366360, ECO:0000269|PubMed:24553177,
FT ECO:0000269|PubMed:24912431"
FT /id="VAR_081114"
FT VARIANT 343..352
FT /note="Missing (in WHIMS1)"
FT /evidence="ECO:0000269|PubMed:12692554"
FT /id="VAR_081115"
FT MUTAGEN 2..9
FT /note="Missing: Reduced CXCL12 binding. Abolishes
FT signaling."
FT /evidence="ECO:0000269|PubMed:10825158"
FT MUTAGEN 4..20
FT /note="Missing: Reduced CXCL12 binding. Impaired signaling.
FT Reduced coreceptor activity for HIV-1 isolates LAI and
FT NDK."
FT /evidence="ECO:0000269|PubMed:10825158"
FT MUTAGEN 7
FT /note="Y->A: Reduced coreceptor activity for HIV-1 isolates
FT LAI and NDK. Greatly reduced coreceptor activity for HIV-1
FT isolates LAI and NDK; when associated with A-12."
FT /evidence="ECO:0000269|PubMed:10825158,
FT ECO:0000269|PubMed:12034737"
FT MUTAGEN 7
FT /note="Y->F: Sulfate incorporation greatly reduced; when
FT associated with F-12 and F-21. Moderate reduction in
FT sulfate incorporation; when associated with F-12 and A-18.
FT No sulfate incorporation and binding SDF-1alpha greatly
FT reduced; when associated with F-12; A-18 and F-21."
FT /evidence="ECO:0000269|PubMed:10825158,
FT ECO:0000269|PubMed:12034737"
FT MUTAGEN 8
FT /note="T->A: No effect on sulfate incorporation; when
FT associated with A-9 and A-13."
FT /evidence="ECO:0000269|PubMed:12034737"
FT MUTAGEN 9
FT /note="S->A: No effect on sulfate incorporation; when
FT associated with A-8 and A-13."
FT /evidence="ECO:0000269|PubMed:12034737"
FT MUTAGEN 10..20
FT /note="Missing: Reduced CXCL12 binding. No effect on
FT signaling."
FT /evidence="ECO:0000269|PubMed:10825158"
FT MUTAGEN 11
FT /note="N->A: Reduced molecular weight. Enhanced coreceptor
FT activity on R5 HIV-1 isolate Envs. Slight further
FT enhancement of coreceptor activity; when associated with A-
FT 13."
FT /evidence="ECO:0000269|PubMed:10756055"
FT MUTAGEN 12
FT /note="Y->A: Greatly reduced coreceptor activity for HIV-1
FT isolates LAI and NDK; when associated with A-7."
FT /evidence="ECO:0000269|PubMed:10825158,
FT ECO:0000269|PubMed:12034737"
FT MUTAGEN 12
FT /note="Y->F: Sulfate incorporation greatly reduced; when
FT associated with F-7 and F-21. Moderate reduction in sulfate
FT incorporation; when associated with F-7 and A-18. No
FT sulfate incorporation and binding SDF-1alpha greatly
FT reduced; when associated with F-7; A-18 and F-21."
FT /evidence="ECO:0000269|PubMed:10825158,
FT ECO:0000269|PubMed:12034737"
FT MUTAGEN 13
FT /note="T->A: Enhanced coreceptor activity on R5 HIV-1
FT isolate Envs. No effect on sulfate incorporation; when
FT associated with A-8 and A-9."
FT /evidence="ECO:0000269|PubMed:10756055"
FT MUTAGEN 14..15
FT /note="EE->AA: Reduced CXCL12 binding. Reduced coreceptor
FT activity for HIV-1 isolate NDK."
FT /evidence="ECO:0000269|PubMed:10825158"
FT MUTAGEN 18
FT /note="S->A: Sulfate incorporation greatly reduced; when
FT associated with F-21. Moderate reduction in sulfate
FT incorporation; when associated with F-7 and F-12. No
FT sulfate incorporation and binding SDF-1alpha greatly
FT reduced; when associated with F-7; F-12; and F-21."
FT /evidence="ECO:0000269|PubMed:12034737"
FT MUTAGEN 21
FT /note="Y->A: Reduced CXCL12 binding. Reduced coreceptor
FT activity for HIV-1 isolates LAI and NDk."
FT /evidence="ECO:0000269|PubMed:10825158,
FT ECO:0000269|PubMed:12034737"
FT MUTAGEN 21
FT /note="Y->F: Sulfate incorporation greatly reduced; when
FT associated with F-7 and F-12. Sulfate incorporation greatly
FT reduced; when associated with A-18. No sulfate
FT incorporation and binding SDF-1alpha greatly reduced; when
FT associated with F-7; F-12 and A-18."
FT /evidence="ECO:0000269|PubMed:10825158,
FT ECO:0000269|PubMed:12034737"
FT MUTAGEN 97
FT /note="D->N: Reduced CXCL12 binding. Abolishes signaling.
FT Markedly reduced coreceptor activity for HIV-1 isolate
FT LAI."
FT /evidence="ECO:0000269|PubMed:10825158"
FT MUTAGEN 119
FT /note="N->D: No reduction of agonist-induced G-protein
FT activation."
FT /evidence="ECO:0000269|PubMed:17197449"
FT MUTAGEN 119
FT /note="N->K: Loss of agonist-induced G-protein activation."
FT /evidence="ECO:0000269|PubMed:17197449"
FT MUTAGEN 119
FT /note="N->S: Constitutive G-protein activation, with
FT further activation induced by agonist."
FT /evidence="ECO:0000269|PubMed:17197449"
FT MUTAGEN 125
FT /note="L->W: Increased thermostability."
FT MUTAGEN 133
FT /note="D->N: No reduction of agonist-induced G-protein
FT activation."
FT /evidence="ECO:0000269|PubMed:17197449"
FT MUTAGEN 134
FT /note="R->A: Loss of agonist-induced G-protein activation."
FT /evidence="ECO:0000269|PubMed:17197449"
FT MUTAGEN 135
FT /note="Y->A: No reduction of agonist-induced G-protein
FT activation."
FT /evidence="ECO:0000269|PubMed:17197449"
FT MUTAGEN 171
FT /note="D->N: Reduced coreceptor activity for HIV-1 isolate
FT NDK."
FT /evidence="ECO:0000269|PubMed:10825158"
FT MUTAGEN 176
FT /note="N->A: Enhanced coreceptor activity on R5 HIV-1
FT isolate Envs; when associated with A-11."
FT /evidence="ECO:0000269|PubMed:10756055"
FT MUTAGEN 183
FT /note="R->A: Reduced coreceptor activity for several HIV-1
FT isolates."
FT /evidence="ECO:0000269|PubMed:10074102"
FT MUTAGEN 187
FT /note="D->A: Reduced CXCL12 binding. Abolishes signaling."
FT /evidence="ECO:0000269|PubMed:10825158"
FT MUTAGEN 188
FT /note="R->A: Reduced coreceptor activity for several HIV-1
FT isolates."
FT /evidence="ECO:0000269|PubMed:10074102"
FT MUTAGEN 193
FT /note="D->A,S,N: Greatly reduced coreceptor activity for
FT HIV-1 isolate NDK. Reduced coreceptor activity for several
FT other HIV-1 isolates."
FT /evidence="ECO:0000269|PubMed:10074102,
FT ECO:0000269|PubMed:10825158"
FT MUTAGEN 193
FT /note="D->R: Abolishes coreceptor activity for HIV-1
FT isolate NDK. Reduced coreceptor activity for several other
FT HIV-1 isolates."
FT /evidence="ECO:0000269|PubMed:10074102,
FT ECO:0000269|PubMed:10825158"
FT MUTAGEN 240
FT /note="T->P: Retains ligand-binding affinity but abolishes
FT signaling."
FT MUTAGEN 262
FT /note="D->A: Markedly reduced coreceptor activity for HIV-1
FT isolate LAI."
FT /evidence="ECO:0000269|PubMed:10825158"
FT MUTAGEN 268
FT /note="E->A: Markedly reduced coreceptor activity for HIV-1
FT isolate NDK. Less effect for HIV-1 isolate LAI."
FT /evidence="ECO:0000269|PubMed:10825158"
FT MUTAGEN 288
FT /note="E->Q: Reduced CXCL12 binding. Impaired signaling.
FT Reduced coreceptor activity for HIV-1 isolate LAI. Enhanced
FT coreceptor activity for HIV-1 isolate NDK."
FT /evidence="ECO:0000269|PubMed:10825158"
FT MUTAGEN 310
FT /note="K->R: No effect on ubiquitination by RNF113A."
FT /evidence="ECO:0000269|PubMed:28978524"
FT MUTAGEN 324
FT /note="S->A: Moderate degradation. About 60% reduction in
FT binding ITCH and no ubiquitination nor protein degradation;
FT when associated with A-325."
FT /evidence="ECO:0000269|PubMed:19116316"
FT MUTAGEN 324
FT /note="S->D: Enhanced binding to ITCH. Enhanced binding to
FT ITCH and greatly increased protein degradation; when
FT associated with D-324."
FT /evidence="ECO:0000269|PubMed:19116316"
FT MUTAGEN 324
FT /note="S->D: Enhanced binding to ITCH. Enhanced binding to
FT ITCH and greatly increased protein degradation; when
FT associated with D-325."
FT /evidence="ECO:0000269|PubMed:19116316"
FT MUTAGEN 325
FT /note="S->A: Moderate degradation. About 60% reduction in
FT binding ITCH and no ubiquitination nor protein degradation;
FT when associated with A-324."
FT /evidence="ECO:0000269|PubMed:19116316"
FT MUTAGEN 330
FT /note="S->A: No effect on binding to ITCH."
FT /evidence="ECO:0000269|PubMed:19116316"
FT MUTAGEN 331
FT /note="K->R: Loss of ubiquitination by RNF113A."
FT /evidence="ECO:0000269|PubMed:28978524"
FT CONFLICT 242..244
FT /note="VIL -> IIP (in Ref. 12; AAK29630)"
FT /evidence="ECO:0000305"
FT CONFLICT 278
FT /note="N -> S (in Ref. 13; BAG35177)"
FT /evidence="ECO:0000305"
FT STRAND 9..11
FT /evidence="ECO:0007829|PDB:2K03"
FT STRAND 21..23
FT /evidence="ECO:0007829|PDB:2K03"
FT STRAND 32..35
FT /evidence="ECO:0007829|PDB:2K05"
FT HELIX 37..62
FT /evidence="ECO:0007829|PDB:3ODU"
FT TURN 63..66
FT /evidence="ECO:0007829|PDB:3ODU"
FT STRAND 67..69
FT /evidence="ECO:0007829|PDB:3OE6"
FT HELIX 72..88
FT /evidence="ECO:0007829|PDB:3ODU"
FT HELIX 91..99
FT /evidence="ECO:0007829|PDB:3ODU"
FT HELIX 105..139
FT /evidence="ECO:0007829|PDB:3ODU"
FT HELIX 141..143
FT /evidence="ECO:0007829|PDB:3OE0"
FT HELIX 145..153
FT /evidence="ECO:0007829|PDB:3ODU"
FT HELIX 155..159
FT /evidence="ECO:0007829|PDB:3ODU"
FT HELIX 161..166
FT /evidence="ECO:0007829|PDB:3ODU"
FT HELIX 169..174
FT /evidence="ECO:0007829|PDB:3ODU"
FT STRAND 175..179
FT /evidence="ECO:0007829|PDB:3ODU"
FT STRAND 181..188
FT /evidence="ECO:0007829|PDB:3ODU"
FT HELIX 193..207
FT /evidence="ECO:0007829|PDB:3ODU"
FT HELIX 209..225
FT /evidence="ECO:0007829|PDB:3ODU"
FT HELIX 226..228
FT /evidence="ECO:0007829|PDB:3ODU"
FT HELIX 231..266
FT /evidence="ECO:0007829|PDB:3ODU"
FT HELIX 274..291
FT /evidence="ECO:0007829|PDB:3ODU"
FT HELIX 294..301
FT /evidence="ECO:0007829|PDB:3ODU"
FT TURN 302..306
FT /evidence="ECO:0007829|PDB:3ODU"
FT HELIX 313..317
FT /evidence="ECO:0007829|PDB:3ODU"
SQ SEQUENCE 352 AA; 39746 MW; 8C8476A186786B83 CRC64;
MEGISIYTSD NYTEEMGSGD YDSMKEPCFR EENANFNKIF LPTIYSIIFL TGIVGNGLVI
LVMGYQKKLR SMTDKYRLHL SVADLLFVIT LPFWAVDAVA NWYFGNFLCK AVHVIYTVNL
YSSVLILAFI SLDRYLAIVH ATNSQRPRKL LAEKVVYVGV WIPALLLTIP DFIFANVSEA
DDRYICDRFY PNDLWVVVFQ FQHIMVGLIL PGIVILSCYC IIISKLSHSK GHQKRKALKT
TVILILAFFA CWLPYYIGIS IDSFILLEII KQGCEFENTV HKWISITEAL AFFHCCLNPI
LYAFLGAKFK TSAQHALTSV SRGSSLKILS KGKRGGHSSV STESESSSFH SS
