Lymphocyte antigen 96 explained

Lymphocyte antigen 96, also known as "Myeloid Differentiation factor 2 (MD-2)," is a protein that in humans is encoded by the LY96 gene.^{[1] [2] [3] [4]}

The protein encoded by this gene is involved in binding lipopolysaccharide with 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. That is, the primary interface between TLR4 and MD-2 is formed before binding LPS and the dimerization interface is induced by binding LPS.

Structure

MD-2 has a β-cup fold structure composed of two anti-parallel β sheets forming a large hydrophobic pocket for ligand binding.^{[5] [6]}

Interactions

Lymphocyte antigen 96 has been shown to interact with TLR 4.^[7]

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. Macrophages in MD-2 knockout mice are unresponsive to LPS.^[8]

LPS is extracted from the bacterial membrane and transferred to TLR4-MD-2 by two accessory proteins, LPS-binding protein and CD14, to induce innate immune response.

Further reading

• Kato K, Morrison AM, Nakano T, Tashiro K, Honjo T . ESOP-1, a secreted protein expressed in the hematopoietic, nervous, and reproductive systems of embryonic and adult mice . Blood . 96 . 1 . 362–4 . July 2000 . 10891475 . 10.1182/blood.V96.1.362.
• Dziarski R, Wang Q, Miyake K, Kirschning CJ, Gupta D . Roman Dziarski. 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 of Immunology . 166 . 3 . 1938–44 . February 2001 . 11160242 . 10.4049/jimmunol.166.3.1938 . free .
• Schromm AB, Lien E, Henneke P, Chow JC, Yoshimura A, Heine H, Latz E, Monks BG, Schwartz DA, Miyake K, Golenbock DT . Molecular genetic analysis of an endotoxin nonresponder mutant cell line: a point mutation in a conserved region of MD-2 abolishes endotoxin-induced signaling . The Journal of Experimental Medicine . 194 . 1 . 79–88 . July 2001 . 11435474 . 2193443 . 10.1084/jem.194.1.79 .
• Visintin A, Mazzoni A, Spitzer JA, Segal DM . Secreted MD-2 is a large polymeric protein that efficiently confers lipopolysaccharide sensitivity to Toll-like receptor 4 . Proceedings of the National Academy of Sciences of the United States of America . 98 . 21 . 12156–61 . October 2001 . 11593030 . 59784 . 10.1073/pnas.211445098 . free . 2001PNAS...9812156V .
• Akashi S, Nagai Y, Ogata H, Oikawa M, Fukase K, Kusumoto S, Kawasaki K, Nishijima M, Hayashi S, Kimoto M, Miyake K . Human MD-2 confers on mouse Toll-like receptor 4 species-specific lipopolysaccharide recognition . . 13 . 12 . 1595–9 . December 2001 . 11717200 . 10.1093/intimm/13.12.1595 . free .
• Abreu MT, Arnold ET, Thomas LS, Gonsky R, Zhou Y, Hu B, Arditi M . TLR4 and MD-2 expression is regulated by immune-mediated signals in human intestinal epithelial cells . The Journal of Biological Chemistry . 277 . 23 . 20431–7 . June 2002 . 11923281 . 10.1074/jbc.M110333200 . free .
• Re F, Strominger JL . Monomeric recombinant MD-2 binds toll-like receptor 4 tightly and confers lipopolysaccharide responsiveness . The Journal of Biological Chemistry . 277 . 26 . 23427–32 . June 2002 . 11976338 . 10.1074/jbc.M202554200 . free .
• Latz E, Visintin A, Lien E, Fitzgerald KA, Monks BG, Kurt-Jones EA, Golenbock DT, Espevik T . 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 . The Journal of Biological Chemistry . 277 . 49 . 47834–43 . December 2002 . 12324469 . 10.1074/jbc.M207873200 . free .
• Schröder NW, Morath S, Alexander C, Hamann L, Hartung T, Zähringer U, Göbel UB, Weber JR, Schumann RR . 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 . The Journal of Biological Chemistry . 278 . 18 . 15587–94 . May 2003 . 12594207 . 10.1074/jbc.M212829200 . free .
• Mullen GE, Kennedy MN, Visintin A, Mazzoni A, Leifer CA, Davies DR, Segal DM . The role of disulfide bonds in the assembly and function of MD-2 . Proceedings of the National Academy of Sciences of the United States of America . 100 . 7 . 3919–24 . April 2003 . 12642668 . 153023 . 10.1073/pnas.0630495100 . free . 2003PNAS..100.3919M .
• Ohnishi T, Muroi M, Tanamoto K . MD-2 is necessary for the toll-like receptor 4 protein to undergo glycosylation essential for its translocation to the cell surface . Clinical and Diagnostic Laboratory Immunology . 10 . 3 . 405–10 . May 2003 . 12738639 . 154975 . 10.1128/cdli.10.3.405-410.2003 .
• Thompson PA, Tobias PS, Viriyakosol S, Kirkland TN, Kitchens RL . Lipopolysaccharide (LPS)-binding protein inhibits responses to cell-bound LPS . The Journal of Biological Chemistry . 278 . 31 . 28367–71 . August 2003 . 12754215 . 10.1074/jbc.M302921200 . free .
• Visintin A, Latz E, Monks BG, Espevik T, Golenbock DT . Lysines 128 and 132 enable lipopolysaccharide binding to MD-2, leading to Toll-like receptor-4 aggregation and signal transduction . The Journal of Biological Chemistry . 278 . 48 . 48313–20 . November 2003 . 12960171 . 10.1074/jbc.M306802200 . free .
• Re F, Strominger JL . Separate functional domains of human MD-2 mediate Toll-like receptor 4-binding and lipopolysaccharide responsiveness . Journal of Immunology . 171 . 10 . 5272–6 . November 2003 . 14607928 . 10.4049/jimmunol.171.10.5272 . free .
• Hamann L, Kumpf O, Müller M, Visintin A, Eckert J, Schlag PM, Schumann RR . A coding mutation within the first exon of the human MD-2 gene results in decreased lipopolysaccharide-induced signaling . Genes and Immunity . 5 . 4 . 283–8 . June 2004 . 15057266 . 10.1038/sj.gene.6364068 . free .
• Gruber A, Mancek M, Wagner H, Kirschning CJ, Jerala R . Structural model of MD-2 and functional role of its basic amino acid clusters involved in cellular lipopolysaccharide recognition . The Journal of Biological Chemistry . 279 . 27 . 28475–82 . July 2004 . 15111623 . 10.1074/jbc.M400993200 . free .
• Cario E, Golenbock DT, Visintin A, Rünzi M, Gerken G, Podolsky DK . Trypsin-sensitive modulation of intestinal epithelial MD-2 as mechanism of lipopolysaccharide tolerance . Journal of Immunology . 176 . 7 . 4258–66 . April 2006 . 16547263 . 10.4049/jimmunol.176.7.4258 . free .
• Jia HP, Kline JN, Penisten A, Apicella MA, Gioannini TL, Weiss J, McCray PB . Endotoxin responsiveness of human airway epithelia is limited by low expression of MD-2 . American Journal of Physiology. Lung Cellular and Molecular Physiology . 287 . 2 . L428-37 . August 2004 . 15121639 . 10.1152/ajplung.00377.2003 . 13203884 .

Notes and References

1. Shimazu R, Akashi S, Ogata H, Nagai Y, Fukudome K, Miyake K, Kimoto M . MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4 . The Journal of Experimental Medicine . 189 . 11 . 1777–82 . June 1999 . 10359581 . 2193086 . 10.1084/jem.189.11.1777 .
2. Abreu MT, Vora P, Faure E, Thomas LS, Arnold ET, Arditi M . 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 of Immunology . 167 . 3 . 1609–16 . August 2001 . 11466383 . 10.4049/jimmunol.167.3.1609 . free .
3. Web site: Entrez Gene: LY96 lymphocyte antigen 96.
4. Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO . The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex . Nature . 458 . 7242 . 1191–5 . April 2009 . 19252480 . 10.1038/nature07830 . 2009Natur.458.1191P . 4396446 .
5. Kim HM, Park BS, Kim JI, Kim SE, Lee J, Oh SC, Enkhbayar P, Matsushima N, Lee H, Yoo OJ, Lee JO . Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran . Cell . 130 . 5 . 906–17 . September 2007 . 17803912 . 10.1016/j.cell.2007.08.002 . 18948568 . free .
6. Ohto U, Fukase K, Miyake K, Satow Y . Crystal structures of human MD-2 and its complex with antiendotoxic lipid IVa . Science . 316 . 5831 . 1632–4 . June 2007 . 17569869 . 10.1126/science.1139111 . 2007Sci...316.1632O . 37539892 .
7. Re F, Strominger JL . Monomeric recombinant MD-2 binds toll-like receptor 4 tightly and confers lipopolysaccharide responsiveness . The Journal of Biological Chemistry . 277 . 26 . 23427–32 . June 2002 . 11976338 . 10.1074/jbc.M202554200 . free .
8. Ciesielska A, Matyjek M, Kwiatkowska K . TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling . . 78 . 4 . 1233–1261 . 2021 . 10.1007/s00018-020-03656-y . 7904555 . 33057840.