TLRs are embedded in the membrane via a single-membrane spanning region of approximately 20 amino acids. The TLR family members that recognize lipid or protein ligands are generally positioned at the cell surface, whereas TLRs that bind nucleic acid motifs are located in endosomes. Some TLRs appear in a soluble form. The soluble TLRs originate from enzymatic cleavage of the full-length receptor (TLR2), alternative splicing of the TLR gene (TLR4), or from a separate gene (TLR5). Both soluble TLR2 and TLR4 reduce the response of their membrane-bound form, and thus may act as decoy receptors that prevent an excessive response to their TLR ligands. Soluble TLR5, however, enhances the reactivity of membrane-bound TLR5 and might therefore aid in microbial detection. Soluble TLRs thus provide an additional form of structural TLR diversity.
