High-density lipoprotein mediates silica nanoparticle recognition by the multi-ligand receptor SR-B1

Scavenger receptor class B type 1 (SR-B1), best known as a high-density lipoprotein (HDL) receptor, is now recognized as a multi-ligand membrane receptor. In addition to HDL, SR-B1 binds low-density lipoprotein (LDL), hepatitis C virus, Gram-positive and Gram-negative bacteria, and inorganic silica particles. However, the mechanisms by which SR-B1 recognizes diverse ligands remain unclear. We previously reported that a basic amino acid cluster consisting of K151, K156, and K395 at the extracellular apex of SR-B1 is essential for charge-dependent binding to silica and is distinct from the known HDL-binding site. In this study, homology modeling of SR-B1 revealed the HDL-binding site is oriented toward the basic cluster. Site-directed mutagenesis demonstrated that this basic cluster is required for HDL and, to a lesser extent, LDL binding, which in turn promotes binding to silica nanoparticles. The selective binding of SR-B1 to silica nanoparticles, but not to TiO₂ nanoparticles, latex nanoparticles, monosodium urate crystals, or multiwalled carbon nanotubes, depends on specific HDL- or LDL-silica interactions. These findings suggest that HDL, and potentially LDL, may underlie SR-B1's function as a muti-ligand membrane receptor.