Functional mimicry of the LDL receptor-associated protein through multimerization of a minimized third domain

• Published in: Biochemical and biophysical research communications Vol. 364; no. 3; pp. 614 - 619
• Main Authors: Isbell, Sara L., Haslam, Simone B., Dennis, Sandra J., Nash, John A., Zankel, Todd C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.12.2007
• Subjects: Animals; Avidity; Delivery; Dimerization; LDL-Receptor Related Protein-Associated Protein - chemistry; LDL-Receptor Related Protein-Associated Protein - metabolism; Liver; LRP1; Male; Multimer; Organ Specificity; Protein Isoforms - chemistry; Protein Isoforms - metabolism; Protein Structure, Tertiary; RAP; Rats; Rats, Sprague-Dawley; Receptor-associated protein; Targeting; Tissue Distribution; RAP; Multimer; LRP1; Targeting; Liver; Avidity; Delivery; Receptor-associated protein
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2007.10.055

The LDL receptor-associated protein (RAP) is a ligand for the LDL receptor-related protein (LRP1). The first and third domains of RAP can each bind to one of many sequence-related pairs of complement-type repeats (CR) found within the LRP1 ectodomain. Multiple sites of interaction between the multivalent RAP ligand and the multivalent LRP1 receptor yield strong binding avidity for the complex. The third domain of RAP can be significantly truncated, with material retention of monovalent CR pair-binding affinity, provided that the minimized sequence is stabilized with an intramolecular disulfide bond. We demonstrate that the avidity of full-length RAP for LRP1 in vitro can be partially reconstituted by assembly of truncated, disulfide-linked RAP peptides on tetravalent streptavidin or bivalent immunoglobulin scaffolds. The peptide complex with streptavidin shows pronounced hepatotropism in vivo, replicating the biodistribution of full-length RAP.