View source for Lymphocyte antigen 96

{{Short description|Protein-coding gene in the species Homo sapiens}}
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{{Infobox_gene}}
'''Lymphocyte antigen 96''', also known as "'''Myeloid Differentiation factor 2 (MD-2)'''," is a [[protein]] that in humans is encoded by the ''LY96'' [[gene]].<ref name="pmid10359581">{{cite journal | vauthors = Shimazu R, Akashi S, Ogata H, Nagai Y, Fukudome K, Miyake K, Kimoto M | title = MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4 | journal = The Journal of Experimental Medicine | volume = 189 | issue = 11 | pages = 1777–82 | date = June 1999 | pmid = 10359581 | pmc = 2193086 | doi = 10.1084/jem.189.11.1777 }}</ref><ref name="pmid11466383">{{cite journal | vauthors = Abreu MT, Vora P, Faure E, Thomas LS, Arnold ET, Arditi M | title = Decreased expression of Toll-like receptor-4 and MD-2 correlates with intestinal epithelial cell protection against dysregulated proinflammatory gene expression in response to bacterial lipopolysaccharide | journal = Journal of Immunology | volume = 167 | issue = 3 | pages = 1609–16 | date = August 2001 | pmid = 11466383 | doi = 10.4049/jimmunol.167.3.1609 | doi-access = free }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: LY96 lymphocyte antigen 96| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23643}}</ref><ref name=":0">{{cite journal | vauthors = Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO | title = The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex | journal = Nature | volume = 458 | issue = 7242 | pages = 1191–5 | date = April 2009 | pmid = 19252480 | doi = 10.1038/nature07830 | bibcode = 2009Natur.458.1191P | s2cid = 4396446 }}</ref>
The [[protein]] encoded by this gene is involved in binding [[lipopolysaccharide]] with [[TLR4|Toll-Like Receptor (TLR4)]].
== Function ==
The MD-2 protein appears to associate with toll-like receptor 4 on the cell surface and confers responsiveness to lipopolysaccharide (LPS), thus providing a link between the receptor and LPS signaling.<ref name="entrez" /> That is, the primary interface between TLR4 and MD-2 is formed before binding LPS and the dimerization interface is induced by binding LPS.<ref name=":0" />
== Structure ==
MD-2 has a β-cup fold structure composed of two anti-parallel [[β sheet]]s forming a large hydrophobic pocket for [[ligand (biochemistry)|ligand]] binding.<ref>{{cite journal | vauthors = Kim HM, Park BS, Kim JI, Kim SE, Lee J, Oh SC, Enkhbayar P, Matsushima N, Lee H, Yoo OJ, Lee JO | title = Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran | journal = Cell | volume = 130 | issue = 5 | pages = 906–17 | date = September 2007 | pmid = 17803912 | doi = 10.1016/j.cell.2007.08.002 | s2cid = 18948568 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Ohto U, Fukase K, Miyake K, Satow Y | title = Crystal structures of human MD-2 and its complex with antiendotoxic lipid IVa | journal = Science | volume = 316 | issue = 5831 | pages = 1632–4 | date = June 2007 | pmid = 17569869 | doi = 10.1126/science.1139111 | bibcode = 2007Sci...316.1632O | s2cid = 37539892 }}</ref>
== Interactions ==
Lymphocyte antigen 96 has been shown to [[Protein-protein interaction|interact]] with [[TLR 4]].<ref name=pmid10359581 /><ref name=pmid11976338>{{cite journal | vauthors = Re F, Strominger JL | title = Monomeric recombinant MD-2 binds toll-like receptor 4 tightly and confers lipopolysaccharide responsiveness | journal = The Journal of Biological Chemistry | volume = 277 | issue = 26 | pages = 23427–32 | date = June 2002 | pmid = 11976338 | doi = 10.1074/jbc.M202554200 | doi-access = free }}</ref>
When LPS binds to a hydrophobic pocket in MD-2, it directly mediates dimerization of the two TLR4-MD-2 complexes. Thus, MD-2 form a heterodimer that recognizes a common pattern in structurally diverse LPS molecules. These interactions allow TLR4 to recognize LPS.<ref name=":0" /> [[Macrophage]]s in MD-2 [[Knockout mouse|knockout mice]] are unresponsive to LPS.<ref name="pmid33057840">{{cite journal | vauthors = Ciesielska A, Matyjek M, Kwiatkowska K | title = TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling | journal = [[Cellular and Molecular Life Sciences]] | volume = 78 | issue=4 | pages = 1233–1261 | date=2021 | doi = 10.1007/s00018-020-03656-y | pmc=7904555  | pmid = 33057840}}</ref>
LPS is extracted from the bacterial membrane and transferred to TLR4-MD-2 by two accessory proteins, [[Lipopolysaccharide binding protein|LPS-binding protein]] and [[CD14]], to induce [[innate immune response]].<ref name=":0" />
== References ==
{{Reflist}}
== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Kato K, Morrison AM, Nakano T, Tashiro K, Honjo T | title = ESOP-1, a secreted protein expressed in the hematopoietic, nervous, and reproductive systems of embryonic and adult mice | journal = Blood | volume = 96 | issue = 1 | pages = 362–4 | date = July 2000 | pmid = 10891475 | doi =  10.1182/blood.V96.1.362}}
* {{cite journal | vauthors = Dziarski R, Wang Q, Miyake K, Kirschning CJ, Gupta D |author-link=Roman Dziarski| title = MD-2 enables Toll-like receptor 2 (TLR2)-mediated responses to lipopolysaccharide and enhances TLR2-mediated responses to Gram-positive and Gram-negative bacteria and their cell wall components | journal = Journal of Immunology | volume = 166 | issue = 3 | pages = 1938–44 | date = February 2001 | pmid = 11160242 | doi = 10.4049/jimmunol.166.3.1938 | doi-access = free }}
* {{cite journal | vauthors = Schromm AB, Lien E, Henneke P, Chow JC, Yoshimura A, Heine H, Latz E, Monks BG, Schwartz DA, Miyake K, Golenbock DT | title = Molecular genetic analysis of an endotoxin nonresponder mutant cell line: a point mutation in a conserved region of MD-2 abolishes endotoxin-induced signaling | journal = The Journal of Experimental Medicine | volume = 194 | issue = 1 | pages = 79–88 | date = July 2001 | pmid = 11435474 | pmc = 2193443 | doi = 10.1084/jem.194.1.79 }}
* {{cite journal | vauthors = Visintin A, Mazzoni A, Spitzer JA, Segal DM | title = Secreted MD-2 is a large polymeric protein that efficiently confers lipopolysaccharide sensitivity to Toll-like receptor 4 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 21 | pages = 12156–61 | date = October 2001 | pmid = 11593030 | pmc = 59784 | doi = 10.1073/pnas.211445098 | doi-access = free | bibcode = 2001PNAS...9812156V }}
* {{cite journal | vauthors = Akashi S, Nagai Y, Ogata H, Oikawa M, Fukase K, Kusumoto S, Kawasaki K, Nishijima M, Hayashi S, Kimoto M, Miyake K | title = Human MD-2 confers on mouse Toll-like receptor 4 species-specific lipopolysaccharide recognition | journal = [[International Immunology]] | volume = 13 | issue = 12 | pages = 1595–9 | date = December 2001 | pmid = 11717200 | doi = 10.1093/intimm/13.12.1595 | doi-access = free }}
* {{cite journal | vauthors = Abreu MT, Arnold ET, Thomas LS, Gonsky R, Zhou Y, Hu B, Arditi M | title = TLR4 and MD-2 expression is regulated by immune-mediated signals in human intestinal epithelial cells | journal = The Journal of Biological Chemistry | volume = 277 | issue = 23 | pages = 20431–7 | date = June 2002 | pmid = 11923281 | doi = 10.1074/jbc.M110333200 | doi-access = free }}
* {{cite journal | vauthors = Re F, Strominger JL | title = Monomeric recombinant MD-2 binds toll-like receptor 4 tightly and confers lipopolysaccharide responsiveness | journal = The Journal of Biological Chemistry | volume = 277 | issue = 26 | pages = 23427–32 | date = June 2002 | pmid = 11976338 | doi = 10.1074/jbc.M202554200 | doi-access = free }}
* {{cite journal | vauthors = Latz E, Visintin A, Lien E, Fitzgerald KA, Monks BG, Kurt-Jones EA, Golenbock DT, Espevik T | title = Lipopolysaccharide rapidly traffics to and from the Golgi apparatus with the toll-like receptor 4-MD-2-CD14 complex in a process that is distinct from the initiation of signal transduction | journal = The Journal of Biological Chemistry | volume = 277 | issue = 49 | pages = 47834–43 | date = December 2002 | pmid = 12324469 | doi = 10.1074/jbc.M207873200 | doi-access = free }}
* {{cite journal | vauthors = Schröder NW, Morath S, Alexander C, Hamann L, Hartung T, Zähringer U, Göbel UB, Weber JR, Schumann RR | title = Lipoteichoic acid (LTA) of Streptococcus pneumoniae and Staphylococcus aureus activates immune cells via Toll-like receptor (TLR)-2, lipopolysaccharide-binding protein (LBP), and CD14, whereas TLR-4 and MD-2 are not involved | journal = The Journal of Biological Chemistry | volume = 278 | issue = 18 | pages = 15587–94 | date = May 2003 | pmid = 12594207 | doi = 10.1074/jbc.M212829200 | doi-access = free }}
* {{cite journal | vauthors = Mullen GE, Kennedy MN, Visintin A, Mazzoni A, Leifer CA, Davies DR, Segal DM | title = The role of disulfide bonds in the assembly and function of MD-2 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 7 | pages = 3919–24 | date = April 2003 | pmid = 12642668 | pmc = 153023 | doi = 10.1073/pnas.0630495100 | doi-access = free | bibcode = 2003PNAS..100.3919M }}
* {{cite journal | vauthors = Ohnishi T, Muroi M, Tanamoto K | title = MD-2 is necessary for the toll-like receptor 4 protein to undergo glycosylation essential for its translocation to the cell surface | journal = Clinical and Diagnostic Laboratory Immunology | volume = 10 | issue = 3 | pages = 405–10 | date = May 2003 | pmid = 12738639 | pmc = 154975 | doi = 10.1128/cdli.10.3.405-410.2003 }}
* {{cite journal | vauthors = Thompson PA, Tobias PS, Viriyakosol S, Kirkland TN, Kitchens RL | title = Lipopolysaccharide (LPS)-binding protein inhibits responses to cell-bound LPS | journal = The Journal of Biological Chemistry | volume = 278 | issue = 31 | pages = 28367–71 | date = August 2003 | pmid = 12754215 | doi = 10.1074/jbc.M302921200 | doi-access = free }}
* {{cite journal | vauthors = Visintin A, Latz E, Monks BG, Espevik T, Golenbock DT | title = Lysines 128 and 132 enable lipopolysaccharide binding to MD-2, leading to Toll-like receptor-4 aggregation and signal transduction | journal = The Journal of Biological Chemistry | volume = 278 | issue = 48 | pages = 48313–20 | date = November 2003 | pmid = 12960171 | doi = 10.1074/jbc.M306802200 | doi-access = free }}
* {{cite journal | vauthors = Re F, Strominger JL | title = Separate functional domains of human MD-2 mediate Toll-like receptor 4-binding and lipopolysaccharide responsiveness | journal = Journal of Immunology | volume = 171 | issue = 10 | pages = 5272–6 | date = November 2003 | pmid = 14607928 | doi = 10.4049/jimmunol.171.10.5272 | doi-access = free }}
* {{cite journal | vauthors = Hamann L, Kumpf O, Müller M, Visintin A, Eckert J, Schlag PM, Schumann RR | title = A coding mutation within the first exon of the human MD-2 gene results in decreased lipopolysaccharide-induced signaling | journal = Genes and Immunity | volume = 5 | issue = 4 | pages = 283–8 | date = June 2004 | pmid = 15057266 | doi = 10.1038/sj.gene.6364068 | doi-access = free }}
* {{cite journal | vauthors = Gruber A, Mancek M, Wagner H, Kirschning CJ, Jerala R | title = Structural model of MD-2 and functional role of its basic amino acid clusters involved in cellular lipopolysaccharide recognition | journal = The Journal of Biological Chemistry | volume = 279 | issue = 27 | pages = 28475–82 | date = July 2004 | pmid = 15111623 | doi = 10.1074/jbc.M400993200 | doi-access = free }}
* {{cite journal | vauthors = Cario E, Golenbock DT, Visintin A, Rünzi M, Gerken G, Podolsky DK | title = Trypsin-sensitive modulation of intestinal epithelial MD-2 as mechanism of lipopolysaccharide tolerance | journal = Journal of Immunology | volume = 176 | issue = 7 | pages = 4258–66 | date = April 2006 | pmid = 16547263 | doi = 10.4049/jimmunol.176.7.4258 | doi-access = free }}
* {{cite journal | vauthors = Jia HP, Kline JN, Penisten A, Apicella MA, Gioannini TL, Weiss J, McCray PB | title = Endotoxin responsiveness of human airway epithelia is limited by low expression of MD-2 | journal = American Journal of Physiology. Lung Cellular and Molecular Physiology | volume = 287 | issue = 2 | pages = L428-37 | date = August 2004 | pmid = 15121639 | doi = 10.1152/ajplung.00377.2003 | s2cid = 13203884 }}
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[[Image:Toll-like receptor pathways revised.jpg|thumbnail|500px|Signaling pathway of toll-like receptors. Dashed grey lines represent unknown associations]]
== External links ==
* {{MeshName|lymphocyte+antigen+96,+human}}
{{TLR signaling pathway}}