Binding studies of a triple-helical peptide model of macrophage scavenger receptor to tetraplex nucleic acids.

The macrophage scavenger receptor (MSR), involved in the uptake of oxidized LDL, binds a variety of polyanionic ligands, and in particular shows selectivity for tetraplex forms of nucleic acids. The ligand binding region has been shown to lie in the triple-helical collagen-like domain of MSR. A model peptide-nucleic acid system is presented here to clarify how the triple-helical motif of MSR recognizes and binds tetraplex nucleic acids. The triple-helical peptide MSR-1, with the sequence (POG)3PKGQKGEKG(POG)4, contains a nine amino acid basic sequence implicated in MSR ligand binding, flanked by Pro-Hyp-Gly triplets to provide stability. The ability of this triple-helical MSR-1 peptide to bind to and perturb the conformation of nucleic acids in tetraplex, duplex, and single-stranded states was assessed by monitoring changes in the nucleic acid circular dichroism spectrum in the 240-300 nm region. Our results show that the triple-helical MSR-1 peptide binds to tetraplex poly(I) in a stoichiometric manner and is capable of reproducing the discrimination exhibited by the native MSR molecule for tetraplex over double-stranded or single-stranded nucleic acid states. The triple-helical reference peptide (POG)10 does not bind to tetraplex poly(I), suggesting that binding requires the highly basic 9-mer sequence from MSR that is included in MSR-1. The MSR-1 peptide did not perturb the CD spectra of a series of other tetraplex nucleic acids, indicating that it does not model the broader specificity that MSR shows under physiological conditions. Models of possible interactions between a triple-helical peptide and a tetraplex polynucleotide are proposed on the basis of the stoichiometry observed for the complex between triple-helical MSR-1 and tetraplex poly(I).