MD-2, also known as lymphocyte antigen 96 and ESOP-1, is a secreted glycoprotein that shares conserved cysteine residues and significant sequence similarity (23%) with MD-1. The gene of human MD-2 encodes a 160 amino acid residue (aa) precursor protein with a 16 aa signal peptide and a 144 aa mature protein, which contains 2 N-glycosylation sites (1). Recombinant secreted MD-2 has been found to exist as disulfide-linked dimers and oligomers (2).
Both MD-1 and MD-2 are accessory molecules that associate with the extracellular leucine-rich repeats (LRR) of Toll-like receptor (TLR) family members, which are type I transmembrane receptors that regulate innate immune responses to microbial pathogens (3, 4). MD-1 binds to RP105 on B cells and macrophages to form the signaling receptor complex for lipopolysaccharide (LPS), a constituent of the outer membrane of Gram-negative bacteria. Similarly, MD-2 interacts with TLR-4 to form the heteromeric receptor that confers LPS responsiveness. MD-2 also associates with TLR-2, albeit with less avidity, to confer responsiveness to cell wall components from both Gram-positive and Gram-negative bacteria. MD-1 and MD-2 are also required for the correct targeting of the TLRs to the cell surface. Although MD-2 glycosylation is not crucial for its surface expression and interaction with TLR-4, it is required for LPS binding and signaling (5).
