ID LY96_HUMAN Reviewed; 160 AA. AC Q9Y6Y9; B3Y6A5; E5RJJ7; DT 27-MAR-2002, integrated into UniProtKB/Swiss-Prot. DT 18-MAY-2010, sequence version 2. DT 11-NOV-2015, entry version 138. DE RecName: Full=Lymphocyte antigen 96; DE Short=Ly-96; DE AltName: Full=ESOP-1 {ECO:0000303|PubMed:10891475}; DE AltName: Full=Protein MD-2 {ECO:0000303|PubMed:10359581}; DE Flags: Precursor; GN Name=LY96; Synonyms=ESOP1, MD2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT GLY-56, FUNCTION, RP INTERACTION WITH TLR4, AND SUBCELLULAR LOCATION. RC TISSUE=Uterus; RX PubMed=10359581; DOI=10.1084/jem.189.11.1777; RA Shimazu R., Akashi S., Ogata H., Nagai Y., Fukudome K., Miyake K., RA Kimoto M.; RT "MD-2, a molecule that confers lipopolysaccharide responsiveness on RT Toll-like receptor 4."; RL J. Exp. Med. 189:1777-1782(1999). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT GLY-56. RX PubMed=10891475; RA Kato K., Morrison A.M., Nakano T., Tashiro K., Honjo T.; RT "ESOP-1, a secreted protein expressed in the hematopoietic, nervous, RT and reproductive systems of embryonic and adult mice."; RL Blood 96:362-364(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), MUTAGENESIS OF CYS-95, AND RP VARIANT GLY-56. RX PubMed=11435474; DOI=10.1084/jem.194.1.79; RA Schromm A.B., Lien E., Henneke P., Chow J.C., Yoshimura A., Heine H., RA Latz E., Monks B.G., Schwartz D.A., Miyake K., Golenbock D.T.; RT "Molecular genetic analysis of an endotoxin nonresponder mutant cell RT line. A point mutation in a conserved region of MD-2 abolishes RT endotoxin-induced signaling."; RL J. Exp. Med. 194:79-88(2001). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT GLY-56. RX PubMed=18810425; DOI=10.1007/s00251-008-0332-0; RA Nakajima T., Ohtani H., Satta Y., Uno Y., Akari H., Ishida T., RA Kimura A.; RT "Natural selection in the TLR-related genes in the course of primate RT evolution."; RL Immunogenetics 60:727-735(2008). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16421571; DOI=10.1038/nature04406; RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., RA Garber M., Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., RA Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., RA Allen N.R., Anderson S., Asakawa T., Blechschmidt K., Bloom T., RA Borowsky M.L., Butler J., Cook A., Corum B., DeArellano K., RA DeCaprio D., Dooley K.T., Dorris L. III, Engels R., Gloeckner G., RA Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., Jaffe D.B., RA Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P., RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H., RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., RA O'Leary S.B., O'Neill K., Parker S.C.J., Polley A., Raymond C.K., RA Reichwald K., Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., RA Smith C.L., Sneddon T.P., Talamas J.A., Tenzin P., Topham K., RA Venkataraman V., Wen G., Yamazaki S., Young S.K., Zeng Q., RA Zimmer A.R., Rosenthal A., Birren B.W., Platzer M., Shimizu N., RA Lander E.S.; RT "DNA sequence and analysis of human chromosome 8."; RL Nature 439:331-335(2006). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT RP GLY-56. RC TISSUE=Liver; 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP SUBUNIT, AND SUBCELLULAR LOCATION. RX PubMed=11274165; DOI=10.1074/jbc.M009164200; RA da Silva Correia J., Soldau K., Christen U., Tobias P.S., RA Ulevitch R.J.; RT "Lipopolysaccharide is in close proximity to each of the proteins in RT its membrane receptor complex. transfer from CD14 to TLR4 and MD-2."; RL J. Biol. Chem. 276:21129-21135(2001). RN [8] RP INTERACTION WITH TLR2 AND TLR4, AND FUNCTION. RX PubMed=11160242; DOI=10.4049/jimmunol.166.3.1938; RA Dziarski R., Wang Q., Miyake K., Kirschning C.J., Gupta D.; RT "MD-2 enables Toll-like receptor 2 (TLR2)-mediated responses to RT lipopolysaccharide and enhances TLR2-mediated responses to Gram- RT positive and Gram-negative bacteria and their cell wall components."; RL J. Immunol. 166:1938-1944(2001). RN [9] RP DISULFIDE BONDS, GLYCOSYLATION, SUBCELLULAR LOCATION, FUNCTION, AND RP INTERACTION WITH TLR4. RX PubMed=11593030; DOI=10.1073/pnas.211445098; RA Visintin A., Mazzoni A., Spitzer J.A., Segal D.M.; RT "Secreted MD-2 is a large polymeric protein that efficiently confers RT lipopolysaccharide sensitivity to Toll-like receptor 4."; RL Proc. Natl. Acad. Sci. U.S.A. 98:12156-12161(2001). RN [10] RP INTERCHAIN DISULFIDE BOND. RX PubMed=12642668; DOI=10.1073/pnas.0630495100; RA Mullen G.E.D., Kennedy M.N., Visintin A., Mazzoni A., Leifer C.A., RA Davies D.R., Segal D.M.; RT "The role of disulfide bonds in the assembly and function of MD-2."; RL Proc. Natl. Acad. Sci. U.S.A. 100:3919-3924(2003). RN [11] RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 19-158 IN COMPLEX WITH TLR4 RP AND LIPOPOLYSACCHARIDE ANALOG, AND SUBUNIT. RX PubMed=17803912; DOI=10.1016/j.cell.2007.08.002; RA Kim H.M., Park B.S., Kim J.-I., Kim S.E., Lee J., Oh S.C., RA Enkhbayar P., Matsushima N., Lee H., Yoo O.J., Lee J.-O.; RT "Crystal structure of the TLR4-MD-2 complex with bound endotoxin RT antagonist Eritoran."; RL Cell 130:906-917(2007). RN [12] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 17-160 IN COMPLEX WITH LIPID RP IV-A, DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-26 AND ASN-114. RX PubMed=17569869; DOI=10.1126/science.1139111; RA Ohto U., Fukase K., Miyake K., Satow Y.; RT "Crystal structures of human MD-2 and its complex with antiendotoxic RT lipid IVa."; RL Science 316:1632-1634(2007). CC -!- FUNCTION: Binds bacterial lipopolysaccharide (LPS) CC (PubMed:17803912, PubMed:17569869). Cooperates with TLR4 in the CC innate immune response to bacterial lipopolysaccharide (LPS), and CC with TLR2 in the response to cell wall components from Gram- CC positive and Gram-negative bacteria (PubMed:11160242, CC PubMed:11593030). Enhances TLR4-dependent activation of NF-kappa-B CC (PubMed:10359581). Cells expressing both LY96 and TLR4, but not CC TLR4 alone, respond to LPS (PubMed:10359581). CC {ECO:0000269|PubMed:10359581, ECO:0000269|PubMed:11160242, CC ECO:0000269|PubMed:11593030, ECO:0000269|PubMed:17569869, CC ECO:0000269|PubMed:17803912}. CC -!- SUBUNIT: Heterogeneous homopolymer formed from homodimers; CC disulfide-linked (PubMed:11593030, PubMed:12642668). Belongs to CC the lipopolysaccharide (LPS) receptor, a multi-protein complex CC containing at least CD14, LY96 and TLR4 (PubMed:11274165). Binds CC to the extracellular domains of TLR2 and TLR4 (PubMed:10359581, CC PubMed:11593030, PubMed:17803912). Ligand binding induces CC interaction with TLR4 and oligomerization of the complex. CC {ECO:0000269|PubMed:10359581, ECO:0000269|PubMed:11274165, CC ECO:0000269|PubMed:11593030, ECO:0000269|PubMed:17569869, CC ECO:0000269|PubMed:17803912}. CC -!- INTERACTION: CC O00206:TLR4; NbExp=5; IntAct=EBI-1539247, EBI-528701; CC -!- SUBCELLULAR LOCATION: Secreted, extracellular space CC {ECO:0000269|PubMed:10359581, ECO:0000269|PubMed:11593030, CC ECO:0000305|PubMed:11274165}. Secreted CC {ECO:0000269|PubMed:11593030}. Note=Retained in the extracellular CC space at the cell surface by interaction with TLR4 CC (PubMed:10359581). {ECO:0000269|PubMed:10359581, CC ECO:0000269|PubMed:11593030}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q9Y6Y9-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9Y6Y9-2; Sequence=VSP_055045; CC Note=No experimental confirmation available. Gene prediction CC based on EST data.; CC -!- PTM: N-glycosylated; high-mannose. {ECO:0000269|PubMed:11593030, CC ECO:0000269|PubMed:17569869}. 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; AB018549; BAA78717.1; -; mRNA. DR EMBL; AF168121; AAF89635.1; -; mRNA. DR EMBL; AB446498; BAG55275.1; -; mRNA. DR EMBL; AC022868; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC087672; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC020690; AAH20690.1; -; mRNA. DR CCDS; CCDS56540.1; -. [Q9Y6Y9-2] DR CCDS; CCDS6216.1; -. [Q9Y6Y9-1] DR RefSeq; NP_001182726.1; NM_001195797.1. [Q9Y6Y9-2] DR RefSeq; NP_056179.3; NM_015364.4. DR UniGene; Hs.726603; -. DR PDB; 1T2Z; Model; -; A=19-160. DR PDB; 2E56; X-ray; 2.00 A; A=17-160. DR PDB; 2E59; X-ray; 2.21 A; A=17-160. DR PDB; 2Z65; X-ray; 2.70 A; C/D=19-158. DR PDB; 3FXI; X-ray; 3.10 A; C/D=19-160. DR PDB; 3ULA; X-ray; 3.60 A; B/D=19-158. DR PDB; 4G8A; X-ray; 2.40 A; C/D=17-160. DR PDBsum; 1T2Z; -. DR PDBsum; 2E56; -. DR PDBsum; 2E59; -. DR PDBsum; 2Z65; -. DR PDBsum; 3FXI; -. DR PDBsum; 3ULA; -. DR PDBsum; 4G8A; -. DR ProteinModelPortal; Q9Y6Y9; -. DR SMR; Q9Y6Y9; 17-160. DR BioGrid; 117170; 4. DR DIP; DIP-38571N; -. DR IntAct; Q9Y6Y9; 4. DR STRING; 9606.ENSP00000284818; -. DR ChEMBL; CHEMBL3038512; -. DR PhosphoSite; Q9Y6Y9; -. DR BioMuta; LY96; -. DR DMDM; 296434574; -. DR MaxQB; Q9Y6Y9; -. DR PaxDb; Q9Y6Y9; -. DR PRIDE; Q9Y6Y9; -. DR Ensembl; ENST00000284818; ENSP00000284818; ENSG00000154589. [Q9Y6Y9-1] DR Ensembl; ENST00000518893; ENSP00000430533; ENSG00000154589. [Q9Y6Y9-2] DR GeneID; 23643; -. DR KEGG; hsa:23643; -. DR UCSC; uc003yad.3; human. [Q9Y6Y9-1] DR CTD; 23643; -. DR GeneCards; LY96; -. DR HGNC; HGNC:17156; LY96. DR MIM; 605243; gene. DR neXtProt; NX_Q9Y6Y9; -. DR PharmGKB; PA134924906; -. DR eggNOG; ENOG410J4Q5; Eukaryota. DR eggNOG; ENOG411154R; LUCA. DR GeneTree; ENSGT00390000000742; -. DR HOGENOM; HOG000001152; -. DR HOVERGEN; HBG032514; -. DR InParanoid; Q9Y6Y9; -. DR KO; K05400; -. DR OMA; IFTEAQK; -. DR OrthoDB; EOG7QG45N; -. DR PhylomeDB; Q9Y6Y9; -. DR TreeFam; TF335876; -. DR Reactome; R-HSA-140534; Ligand-dependent caspase activation. DR Reactome; R-HSA-166016; Toll Like Receptor 4 (TLR4) Cascade. DR Reactome; R-HSA-166058; MyD88:Mal cascade initiated on plasma membrane. DR Reactome; R-HSA-166166; MyD88-independent TLR3/TLR4 cascade. DR Reactome; R-HSA-2562578; TRIF-mediated programmed cell death. DR Reactome; R-HSA-5602498; MyD88 deficiency (TLR2/4). DR Reactome; R-HSA-5603041; IRAK4 deficiency (TLR2/4). DR Reactome; R-HSA-936964; Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon. DR Reactome; R-HSA-937041; IKK complex recruitment mediated by RIP1. DR Reactome; R-HSA-937072; TRAF6 mediated induction of TAK1 complex. DR EvolutionaryTrace; Q9Y6Y9; -. DR GeneWiki; Lymphocyte_antigen_96; -. DR GenomeRNAi; 23643; -. DR NextBio; 46449; -. DR PRO; PR:Q9Y6Y9; -. DR Proteomes; UP000005640; Chromosome 8. DR Bgee; Q9Y6Y9; -. DR CleanEx; HS_LY96; -. DR Genevisible; Q9Y6Y9; HS. DR GO; GO:0010008; C:endosome membrane; TAS:Reactome. DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-SubCell. DR GO; GO:0031226; C:intrinsic component of plasma membrane; IDA:UniProtKB. DR GO; GO:0046696; C:lipopolysaccharide receptor complex; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0015026; F:coreceptor activity; TAS:ProtInc. DR GO; GO:0001875; F:lipopolysaccharide receptor activity; IDA:UniProtKB. DR GO; GO:0097296; P:activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway; TAS:Reactome. DR GO; GO:0006915; P:apoptotic process; TAS:Reactome. DR GO; GO:0007166; P:cell surface receptor signaling pathway; TAS:ProtInc. DR GO; GO:0006968; P:cellular defense response; TAS:ProtInc. DR GO; GO:0032497; P:detection of lipopolysaccharide; IDA:UniProtKB. DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; TAS:Reactome. DR GO; GO:0007249; P:I-kappaB kinase/NF-kappaB signaling; TAS:Reactome. DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW. DR GO; GO:0045087; P:innate immune response; TAS:Reactome. DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IDA:GOC. DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome. DR GO; GO:0002756; P:MyD88-independent toll-like receptor signaling pathway; TAS:Reactome. DR GO; GO:0031666; P:positive regulation of lipopolysaccharide-mediated signaling pathway; IEA:Ensembl. DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; ISS:UniProtKB. DR GO; GO:0012501; P:programmed cell death; TAS:Reactome. DR GO; GO:0032496; P:response to lipopolysaccharide; IDA:MGI. DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome. DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome. DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; ISS:UniProtKB. DR GO; GO:0002224; P:toll-like receptor signaling pathway; TAS:Reactome. DR GO; GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome. DR GO; GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome. DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome. DR InterPro; IPR014756; Ig_E-set. DR InterPro; IPR003172; ML_dom. DR Pfam; PF02221; E1_DerP2_DerF2; 1. DR SMART; SM00737; ML; 1. DR SUPFAM; SSF81296; SSF81296; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Complete proteome; Disulfide bond; KW Glycoprotein; Immunity; Inflammatory response; Innate immunity; KW Polymorphism; Reference proteome; Secreted; Signal. FT SIGNAL 1 18 {ECO:0000255}. FT CHAIN 19 160 Lymphocyte antigen 96. FT /FTId=PRO_0000018619. FT REGION 119 123 Interaction with lipopolysaccharide. FT {ECO:0000244|PDB:2E56, FT ECO:0000244|PDB:2E59, FT ECO:0000244|PDB:4G8A, FT ECO:0000269|PubMed:17569869, FT ECO:0000269|PubMed:17803912}. FT CARBOHYD 26 26 N-linked (GlcNAc...). FT {ECO:0000244|PDB:2E56, FT ECO:0000244|PDB:2E59, FT ECO:0000269|PubMed:17569869}. FT CARBOHYD 114 114 N-linked (GlcNAc...). FT {ECO:0000244|PDB:2E56, FT ECO:0000244|PDB:2E59, FT ECO:0000269|PubMed:17569869}. FT DISULFID 25 51 {ECO:0000244|PDB:2E56, FT ECO:0000244|PDB:2E59, FT ECO:0000244|PDB:2Z65, FT ECO:0000269|PubMed:17569869, FT ECO:0000269|PubMed:17803912}. FT DISULFID 37 148 {ECO:0000244|PDB:2E56, FT ECO:0000244|PDB:2E59, FT ECO:0000244|PDB:2Z65, FT ECO:0000269|PubMed:17569869, FT ECO:0000269|PubMed:17803912}. FT DISULFID 95 105 {ECO:0000244|PDB:2E56, FT ECO:0000244|PDB:2E59, FT ECO:0000244|PDB:2Z65, FT ECO:0000269|PubMed:17569869, FT ECO:0000269|PubMed:17803912}. FT VAR_SEQ 38 68 DKMQYPISINVNPCIELKRSKGLLHIFYIPR -> G (in FT isoform 2). {ECO:0000305}. FT /FTId=VSP_055045. FT VARIANT 56 56 R -> G (in dbSNP:rs6472812). FT {ECO:0000269|PubMed:10359581, FT ECO:0000269|PubMed:10891475, FT ECO:0000269|PubMed:11435474, FT ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:18810425}. FT /FTId=VAR_050030. FT VARIANT 157 157 P -> S (in dbSNP:rs11466004). FT /FTId=VAR_024532. FT MUTAGEN 95 95 C->Y: Abolishes LPS-response. FT {ECO:0000269|PubMed:11435474}. FT STRAND 22 26 {ECO:0000244|PDB:2E56}. FT STRAND 28 36 {ECO:0000244|PDB:2E56}. FT STRAND 38 40 {ECO:0000244|PDB:4G8A}. FT STRAND 45 50 {ECO:0000244|PDB:2E56}. FT STRAND 57 65 {ECO:0000244|PDB:2E56}. FT STRAND 75 82 {ECO:0000244|PDB:2E56}. FT STRAND 90 93 {ECO:0000244|PDB:2E56}. FT STRAND 97 101 {ECO:0000244|PDB:2E56}. FT HELIX 103 106 {ECO:0000244|PDB:2E56}. FT STRAND 113 121 {ECO:0000244|PDB:2E56}. FT STRAND 129 139 {ECO:0000244|PDB:2E56}. FT TURN 140 143 {ECO:0000244|PDB:2E56}. FT STRAND 144 155 {ECO:0000244|PDB:2E56}. SQ SEQUENCE 160 AA; 18546 MW; 0F92AFF583637C6B CRC64; MLPFLFFSTL FSSIFTEAQK QYWVCNSSDA SISYTYCDKM QYPISINVNP CIELKRSKGL LHIFYIPRRD LKQLYFNLYI TVNTMNLPKR KEVICRGSDD DYSFCRALKG ETVNTTISFS FKGIKFSKGK YKCVVEAISG SPEEMLFCLE FVILHQPNSN //