title: Molecular basis of familial hypercholesterolaemia from structure of LDL receptor module.
abstract: The low-density lipoprotein receptor (LDLR) is responsible for the uptake of cholesterol-containing lipoprotein particles into cells. The amino-terminal region of LDLR, which consists of seven tandemly repeated, approximately 40-amino-acid, cysteine-rich modules (LDL-A modules), mediates binding to lipoproteins. LDL-A modules are biologically ubiquitous domains, found in over 100 proteins in the sequence database. The structure of ligand-binding repeat 5 (LR5) of the LDLR, determined to 1.7 A resolution by X-ray crystallography and presented 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 with the disease familial hypercholesterolaemia alter residues that directly coordinate Ca2+ or that serve as scaffolding residues of LR5.
authors.affiliation: Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge 02142, USA.
authors.forename: D
authors.initials: D
authors.lastname: Fass
authors.forename: S
authors.initials: S
authors.lastname: Blacklow
authors.forename: P S
authors.initials: PS
authors.lastname: Kim
authors.forename: J M
authors.initials: JM
authors.lastname: Berger
mesh_terms: D000595:Amino Acid Sequence; D002118:Calcium / Q000737:chemistry; D018360:Crystallography, X-Ray; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D011973:Receptors, LDL / Q000737:chemistry* / Q000235:genetics
chemical_list: D011973:Receptors, LDL; D002118:Calcium