Lymphocyte antigen 96
Protein-coding gene in the species Homo sapiens
Lymphocyte antigen 96 , also known as "Myeloid Differentiation factor 2 (MD-2) ," is a protein that in humans is encoded by the LY96 gene .[ 5] [ 6] [ 7] [ 8]
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.[ 7] [ 8]
Structure
MD-2 has a β-cup fold structure composed of two anti-parallel β sheets forming a large hydrophobic pocket for ligand binding.[ 9] [ 10]
Interactions
Lymphocyte antigen 96 has been shown to interact with TLR 4 .[ 5] [ 11]
When LPS binds to a hydrophobic pocket in MD-2, it directly mediates dimerization of the two TLR4-MD-2 complexes. Thus, TLR4 and MD-2 form a heterodimer that recognizes a common pattern in structurally diverse LPS molecules. These interactions allow TLR4 to recognize LPS.[ 8] Macrophages in MD-2 knockout mice are unresponsive to LPS.[ 12]
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 .[ 8]
References
^ a b c GRCh38: Ensembl release 89: ENSG00000154589 – Ensembl , May 2017^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025779 – Ensembl , May 2017^ "Human PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .^ "Mouse PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .^ a b Shimazu R, Akashi S, Ogata H, Nagai Y, Fukudome K, Miyake K, et al. (June 1999). "MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4" . The Journal of Experimental Medicine . 189 (11): 1777– 82. doi :10.1084/jem.189.11.1777 . PMC 2193086 PMID 10359581 . ^ Abreu MT, Vora P, Faure E, Thomas LS, Arnold ET, Arditi M (August 2001). "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. doi :10.4049/jimmunol.167.3.1609 PMID 11466383 . ^ a b "Entrez Gene: LY96 lymphocyte antigen 96" .^ a b c d Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO (April 2009). "The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex". Nature . 458 (7242): 1191– 5. Bibcode :2009Natur.458.1191P . doi :10.1038/nature07830 . PMID 19252480 . S2CID 4396446 . ^ Kim HM, Park BS, Kim JI, Kim SE, Lee J, Oh SC, et al. (September 2007). "Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran" . Cell . 130 (5): 906– 17. doi :10.1016/j.cell.2007.08.002 PMID 17803912 . S2CID 18948568 . ^ Ohto U, Fukase K, Miyake K, Satow Y (June 2007). "Crystal structures of human MD-2 and its complex with antiendotoxic lipid IVa". Science . 316 (5831): 1632– 4. Bibcode :2007Sci...316.1632O . doi :10.1126/science.1139111 . PMID 17569869 . S2CID 37539892 . ^ Re F, Strominger JL (June 2002). "Monomeric recombinant MD-2 binds toll-like receptor 4 tightly and confers lipopolysaccharide responsiveness" . The Journal of Biological Chemistry . 277 (26): 23427– 32. doi :10.1074/jbc.M202554200 PMID 11976338 . ^ Ciesielska A, Matyjek M, Kwiatkowska K (2021). "TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling" . Cellular and Molecular Life Sciences 78 (4): 1233– 1261. doi :10.1007/s00018-020-03656-y . PMC 7904555 PMID 33057840 .
Further reading
Kato K, Morrison AM, Nakano T, Tashiro K, Honjo T (July 2000). "ESOP-1, a secreted protein expressed in the hematopoietic, nervous, and reproductive systems of embryonic and adult mice". Blood . 96 (1): 362– 4. doi :10.1182/blood.V96.1.362 . PMID 10891475 . Dziarski R , Wang Q, Miyake K, Kirschning CJ, Gupta D (February 2001). "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. doi :10.4049/jimmunol.166.3.1938 PMID 11160242 .Schromm AB, Lien E, Henneke P, Chow JC, Yoshimura A, Heine H, et al. (July 2001). "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. doi :10.1084/jem.194.1.79 . PMC 2193443 PMID 11435474 . Visintin A, Mazzoni A, Spitzer JA, Segal DM (October 2001). "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. Bibcode :2001PNAS...9812156V . doi :10.1073/pnas.211445098 PMC 59784 PMID 11593030 . Akashi S, Nagai Y, Ogata H, Oikawa M, Fukase K, Kusumoto S, et al. (December 2001). "Human MD-2 confers on mouse Toll-like receptor 4 species-specific lipopolysaccharide recognition" . International Immunology 13 (12): 1595– 9. doi :10.1093/intimm/13.12.1595 PMID 11717200 . Abreu MT, Arnold ET, Thomas LS, Gonsky R, Zhou Y, Hu B, et al. (June 2002). "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. doi :10.1074/jbc.M110333200 PMID 11923281 . Re F, Strominger JL (June 2002). "Monomeric recombinant MD-2 binds toll-like receptor 4 tightly and confers lipopolysaccharide responsiveness" . The Journal of Biological Chemistry . 277 (26): 23427– 32. doi :10.1074/jbc.M202554200 PMID 11976338 . Latz E, Visintin A, Lien E, Fitzgerald KA, Monks BG, Kurt-Jones EA, et al. (December 2002). "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. doi :10.1074/jbc.M207873200 PMID 12324469 . Schröder NW, Morath S, Alexander C, Hamann L, Hartung T, Zähringer U, et al. (May 2003). "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. doi :10.1074/jbc.M212829200 PMID 12594207 . Mullen GE, Kennedy MN, Visintin A, Mazzoni A, Leifer CA, Davies DR, et al. (April 2003). "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. Bibcode :2003PNAS..100.3919M . doi :10.1073/pnas.0630495100 PMC 153023 PMID 12642668 . Ohnishi T, Muroi M, Tanamoto K (May 2003). "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. doi :10.1128/cdli.10.3.405-410.2003 . PMC 154975 PMID 12738639 . Thompson PA, Tobias PS, Viriyakosol S, Kirkland TN, Kitchens RL (August 2003). "Lipopolysaccharide (LPS)-binding protein inhibits responses to cell-bound LPS" . The Journal of Biological Chemistry . 278 (31): 28367– 71. doi :10.1074/jbc.M302921200 PMID 12754215 . Visintin A, Latz E, Monks BG, Espevik T, Golenbock DT (November 2003). "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. doi :10.1074/jbc.M306802200 PMID 12960171 . Re F, Strominger JL (November 2003). "Separate functional domains of human MD-2 mediate Toll-like receptor 4-binding and lipopolysaccharide responsiveness" . Journal of Immunology . 171 (10): 5272– 6. doi :10.4049/jimmunol.171.10.5272 PMID 14607928 . Hamann L, Kumpf O, Müller M, Visintin A, Eckert J, Schlag PM, et al. (June 2004). "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. doi :10.1038/sj.gene.6364068 PMID 15057266 . Gruber A, Mancek M, Wagner H, Kirschning CJ, Jerala R (July 2004). "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. doi :10.1074/jbc.M400993200 PMID 15111623 . Cario E, Golenbock DT, Visintin A, Rünzi M, Gerken G, Podolsky DK (April 2006). "Trypsin-sensitive modulation of intestinal epithelial MD-2 as mechanism of lipopolysaccharide tolerance" . Journal of Immunology . 176 (7): 4258– 66. doi :10.4049/jimmunol.176.7.4258 PMID 16547263 . Jia HP, Kline JN, Penisten A, Apicella MA, Gioannini TL, Weiss J, et al. (August 2004). "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. doi :10.1152/ajplung.00377.2003 . PMID 15121639 . S2CID 13203884 .
Signaling pathway of toll-like receptors. Dashed grey lines represent unknown associations
External links
