Crystal structure of soluble MD-1 and its interaction with lipid IVa.
Lipopolysaccharide (LPS) of Gram-negative bacteria is a common pathogen-associated molecular pattern (PAMP) that induces potent innate immune responses. The host immune response against LPS is triggered by myeloid differentiation factor 2 (MD-2) in association with Toll-like receptor 4 (TLR4) on the cell surface. The MD-2/TLR4-mediated LPS response is regulated by the evolutionarily related complex of MD-1 and Toll-like receptor homolog RP105. Here, we report crystallographic and biophysical data that demonstrate a previously unidentified direct interaction of MD-1 with LPS. The crystal structure of chicken MD-1 (cMD-1) at 2.0 A resolution exhibits a beta-cup-like fold, similar to MD-2, that encloses a hydrophobic cavity between the two beta-sheets. A lipid-like moiety was observed inside the cavity, suggesting the possibility of a direct MD-1/LPS interaction. LPS was subsequently identified as an MD-1 ligand by native gel electrophoresis and gel filtration analyses. The crystal structure of cMD-1 with lipid IVa, an LPS precursor, at 2.4 A resolution revealed that the lipid inserts into the deep hydrophobic cavity of the beta-cup-like structure, but with some important differences compared with MD-2. These findings suggest that soluble MD-1 alone, in addition to its complex with RP105, can regulate host LPS sensitivity.
Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Sung-il
SI
Yoon
Minsun
M
Hong
Gye Won
GW
Han
Ian A
IA
Wilson
D000595:Amino Acid Sequence; D000818:Animals; D000954:Antigens, Surface / Q000737:chemistry* / Q000235:genetics; D030161:Avian Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D001665:Binding Sites; D002645:Chickens / Q000235:genetics / Q000276:immunology; D018360:Crystallography, X-Ray; D006017:Glycolipids / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008050:Lipid A / Q000031:analogs & derivatives* / Q000737:chemistry; D051218:Lymphocyte Antigen 96 / Q000737:chemistry; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D017386:Sequence Homology, Amino Acid; D012995:Solubility; D051197:Toll-Like Receptor 4 / Q000737:chemistry
D000954:Antigens, Surface; D030161:Avian Proteins; D006017:Glycolipids; D008024:Ligands; D008050:Lipid A; D051218:Lymphocyte Antigen 96; D046911:Macromolecular Substances; D011994:Recombinant Proteins; D051197:Toll-Like Receptor 4; C040142:lipid A precursors, bacterial