Lymphocyte antigen 96

Lymphocyte antigen 96, also known as "Myeloid Differentiation factor 2 (MD-2)," is a protein that in humans is encoded by the LY96 gene.

LY96
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2E56, 2E59, 2Z65, 3FXI, 3ULA, 4G8A
Identifiers
Aliases	LY96, ESOP-1, MD-2, MD2, ly-96, lymphocyte antigen 96
External IDs	OMIM: 605243; MGI: 1341909; HomoloGene: 9109; GeneCards: LY96; OMA:LY96 - orthologs
Gene location (Human) Chr. Chromosome 8 (human) Band 8q21.11 Start 73,991,392 bp End 74,029,079 bp
Gene location (Mouse) Chr. Chromosome 1 (mouse) Band 1|1 A3 Start 16,758,275 bp End 16,779,835 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte periodontal fiber granulocyte spleen testicle appendix lymph node gallbladder decidua trabecular bone Top expressed in blastocyst granulocyte morula right kidney zygote seminal vesicula parotid gland epithelium of small intestine proximal tubule embryo More reference expression data BioGPS More reference expression data
Gene ontology Molecular function coreceptor activity protein binding lipopolysaccharide immune receptor activity lipopolysaccharide binding Toll-like receptor 4 binding Cellular component intrinsic component of plasma membrane plasma membrane extracellular region lipopolysaccharide receptor complex endosome membrane extracellular space Biological process toll-like receptor 4 signaling pathway immune system process MyD88-dependent toll-like receptor signaling pathway positive regulation of lipopolysaccharide-mediated signaling pathway TRIF-dependent toll-like receptor signaling pathway cellular defense response cell surface receptor signaling pathway response to lipopolysaccharide positive regulation of tumor necrosis factor production inflammatory response cellular response to lipopolysaccharide detection of lipopolysaccharide I-kappaB kinase/NF-kappaB signaling MyD88-independent toll-like receptor signaling pathway lipopolysaccharide-mediated signaling pathway negative regulation of MyD88-independent toll-like receptor signaling pathway innate immune response necroptosis apoptotic signaling pathway toll-like receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 23643 17087 Ensembl ENSG00000154589 ENSMUSG00000025779 UniProt Q9Y6Y9 Q9JHF9 RefSeq (mRNA) NM_001195797 NM_015364 NM_001159711 NM_016923 RefSeq (protein) NP_001182726 NP_056179 NP_001153183 NP_058619 Location (UCSC) Chr 8: 73.99 – 74.03 Mb Chr 1: 16.76 – 16.78 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

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.

Interactions

Lymphocyte antigen 96 has been shown to interact with TLR 4.

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. Macrophages in MD-2 knockout mice are unresponsive to LPS.

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 (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 12863207.
• 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

• lymphocyte antigen 96, human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)