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 27-MAR-2024, entry version 202. 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 UBIQUITINATION BY ITCH. RX PubMed=34927784; DOI=10.15252/embr.202051182; RA Tsunoda T., Riku M., Yamada N., Tsuchiya H., Tomita T., Suzuki M., RA Kizuki M., Inoko A., Ito H., Murotani K., Murakami H., Saeki Y., Kasai K.; RT "ENTREP/FAM189A2 encodes a new ITCH ubiquitin ligase activator that is RT downregulated in breast cancer."; RL EMBO Rep. 23:e51182-e51182(2022). RN [59] 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 [60] 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 [61] {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 [62] 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; Sequence=Displayed; CC Name=2; Synonyms=CXCR4-LO; CC IsoId=P61073-2, P30991-2; 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 (PubMed:14602072, PubMed:34927784). The ubiquitin- CC dependent mechanism, endosomal sorting complex required for transport CC (ESCRT), then targets CXCR4 for lysosomal degradation. This process is CC dependent also on prior Ser-/Thr-phosphorylation in the C-terminal of CC CXCR4. Also binding of ARRB1 to STAM negatively regulates CXCR4 sorting CC to lysosomes though modulating ubiquitination of SFR5S. CC {ECO:0000269|PubMed:14602072, ECO:0000269|PubMed:28978524, CC ECO:0000269|PubMed:34927784}. 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, PubMed:8234909). Later reports CC showed that it acts as a receptor for the C-X-C chemokine CXCL12/SDF-1 CC (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/"; 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; 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 PDB; 8GP3; EM; 4.80 A; U/V=336-352. DR PDB; 8I0Q; EM; 4.45 A; U/V=336-352. 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 PDBsum; 8GP3; -. DR PDBsum; 8I0Q; -. DR AlphaFoldDB; P61073; -. DR BMRB; P61073; -. DR SMR; P61073; -. DR BioGRID; 113607; 245. DR CORUM; P61073; -. DR DIP; DIP-34773N; -. DR DIP; DIP-46290N; -. DR IntAct; P61073; 42. DR MINT; P61073; -. DR STRING; 9606.ENSP00000386884; -. DR BindingDB; P61073; -. DR ChEMBL; CHEMBL2107; -. DR DrugBank; DB05501; AMD-070. DR DrugBank; DB00181; Baclofen. DR DrugBank; DB00452; Framycetin. DR DrugBank; DB12698; Ibalizumab. DR DrugBank; DB12715; MSX-122. DR DrugBank; DB06809; Plerixafor. DR DrugBank; DB12018; Ulocuplumab. DR DrugCentral; P61073; -. DR GuidetoPHARMACOLOGY; 71; -. DR TCDB; 9.A.14.13.17; the g-protein-coupled receptor (gpcr) family. DR GlyCosmos; P61073; 3 sites, No reported glycans. 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; 9606-ENSP00000386884; -. DR PeptideAtlas; P61073; -. DR ProteomicsDB; 57256; -. DR ProteomicsDB; 57257; -. [P61073-2] DR Pumba; P61073; -. DR ABCD; P61073; 38 sequenced antibodies. DR Antibodypedia; 4421; 2070 antibodies from 53 providers. DR DNASU; 7852; -. DR Ensembl; ENST00000241393.4; ENSP00000241393.3; ENSG00000121966.8. [P61073-1] DR Ensembl; ENST00000409817.1; ENSP00000386884.1; ENSG00000121966.8. [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 AGR; HGNC:2561; -. 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; GDYEEPC; -. DR OrthoDB; 4062414at2759; -. 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 Reactome; R-HSA-9823730; Formation of definitive endoderm. DR Reactome; R-HSA-9827857; Specification of primordial germ cells. DR SignaLink; P61073; -. DR SIGNOR; P61073; -. DR BioGRID-ORCS; 7852; 8 hits in 1158 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 199 other cell types or tissues. 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:0005770; C:late endosome; IDA:UniProtKB. DR GO; GO:0005764; C:lysosome; IDA:UniProtKB. 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; TAS:ProtInc. 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:0071417; P:cellular response to organonitrogen compound; IEA:Ensembl. 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:0030335; P:positive regulation of cell migration; IMP:BHF-UCL. 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:1904018; P:positive regulation of vasculature development; IMP:BHF-UCL. 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:1901327; P:response to tacrolimus; 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 CDD; cd15179; 7tmA_CXCR4; 1. DR DisProt; DP01249; -. DR Gene3D; 1.20.1070.10; Rhodopsin 7-helix transmembrane proteins; 1. 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 PANTHER; PTHR10489:SF594; C-X-C CHEMOKINE RECEPTOR TYPE 4; 1. DR PANTHER; PTHR10489; CELL ADHESION MOLECULE; 1. 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 SUPFAM; SSF81321; Family A G protein-coupled receptor-like; 1. DR PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1. DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1. DR Genevisible; P61073; HS. 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 FT A-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-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 325 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 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 //