1988 Discovery of the LDL receptor-related protein (LRP). One of the largest membrane proteins to date, LRP was found using a homology screening approach against the most conserved sequences in the LDL receptor ligand binding domain. Because of its striking structural similarity to the LDL receptor, in particular the presence of 4 highly conserved ligand binding domains, LRP was proposed to function as a hypothetical chylomicron remnant receptor that, in concert with the LDL receptor, was thought to mediate the removal of dietary cholesterol by the liver.

1989 LRP functions as a receptor for ApoE in vitro and in cultured cells.

1992 Disruption of the LRP gene in the mouse by homologous recombination reveals an essential function during embryonic development.

1993 Recombinant adenovirus can serve as an efficient gene transfer vehicle for overexpression of the LDL receptor in mouse liver.

1993 Generation of LDL receptor-deficient mice as a small animal model of human hypercholesterolemia. Recombinant adenovirus corrects LDL receptor deficiency in knockout mice.

1994 Gene transfer of an endogenous inhibitor of ligand binding to LRP using recombinant adenovirus results in the accumulation of remnant lipoproteins in the circulation of LDL receptor knockout mice.

1995 Genetic disruption of RAP, a molecular chaperone for LRP, results in impaired production of LRP and a related receptor, megalin

1996 Genetic disruption of the LDL receptor family member megalin causes holoprosencephaly, a frequent genetic malformation of human newborns.

1998 Definitive evidence for a function of LRP as a chylomicron remnant receptor was obtained in genetically altered mice in which LRP could be conditionally inactivated in the liver.

1998 A class of cytoplasmic adaptor proteins containing PTB protein interaction domains is shown to interact with the cytoplasmic tail of LDL receptor family members and the amyloid precursor protein.