MOLECULAR-BASIS OF FAMILIAL HYPERCHOLESTEROLEMIA FROM STRUCTURE OF LDL RECEPTOR MODULE

The low-density lipoprotein receptor (LDLR) is responsible for the upt ake of cholesterol-containing lipoprotein particles into cells(1,2). T he amino-terminal region of LDLR, which consists of seven tandemly rep eated, similar to 40-amino-acid, cysteine-rich modules (LDL-A modules) , mediates binding to lipoproteins(3,4). LDL-A modules are biologicall y ubiquitous domains, found in over 100 proteins in the sequence datab ase(5). The structure of ligand-binding repeat 5 (LR5) of the LDLR, de termined to 1.7 Angstrom resolution by X-ray crystallography and prese nted here, contains a calcium ion coordinated by acidic residues that lie at the carboxy-terminal end of the domain and are conserved among LDL-A modules. Naturally occurring point mutations found in patients w ith the disease familial hypercholesterolaemia(6) alter residues that directly coordinate Ca2+ or that serve as scaffolding residues of LR5.