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MD-2 is a member of the Toll/interleukin-1 receptor (TIR) family, a group of proteins that include the Toll-like receptors (TLRs). TLRs are signaling molecules that recognize different pathogen-associated molecular patterns (PAMPs) and serve as an important link between the innate and adaptive immune responses. TLR4, the major signaling receptor for lipopolysaccharide (LPS), requires the binding of MD-2 to its extracellular region for maximal response to LPS. The specificity of this response is determined by the species of MD-2; e.g., human MD-2 can cause mouse TLR4 to react to LPS analogs that are normally antagonistic to human but not mouse TLR4.