MD-2 provides crucial stabilization that supports the formation of TLR4/MD-2 heterodimer with nickel or cobalt ions.

<p>(A) A ribbon representation of a TLR4/MD-2 heterodimer (pdb id 3fxi). Amino acid residues of both TLR4 and MD-2 that form hydrophobic interactions with each other are shown as spheres and indicated with arrows. (B) A ribbon representation of the intrinsic dimerization interface between both TLR4 ectodomains. Amino acid residues that engage in direct interactions with one another are shown as spheres. Histidines H431, H456 and H458 are represented as sticks and colored orange. Green spheres represent metal ions that are coordinated between the indicated histidines. (C) A ribbon representation of TLR4 dimer without MD-2 shown from a top view. Without MD-2 both TLR4 ectodomains lack proper stabilization and can wobble around one another, causing disruption of a proper conformation that would enable cytoplasmic TIR domain dimerization and consecutive triggering of the TLR4 receptor signaling pathway. Figures were prepared with the UCSF Chimera package [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120583#pone.0120583.ref031" target="_blank">31</a>].