We report herein the cDNA cloning of a novel member of the low-density lipoprotein receptor (LDLR) family termed LDLR-related protein 3 (LRP3). Human and rat LRP3 cDNAs encode a 770-amino-acid type 1 membrane protein with the following regions: a putative signal sequence, two isoleucine/leucine/valine-rich regions with an RGD sequence, two ligand-binding repeat regions, a putative transmembrane region, and a proline-rich cytoplasmic region with a tyrosine-based internalization signal. Fluorescence in situ hybridization of human chromosomes revealed that the human LRP3 gene mapped to chromosome bands 19q12-q13.2. LRP3 transcript was detected in a wide range of human tissues, with the highest expression in skeletal muscle and ovary. Despite the presence of the ligand-binding repeats, CHO cells transfected with LRP3 did not bind beta-migrating very-low-density lipoprotein or receptor-associated protein. (C) 1998 Academic Press.