Molecular basis of familial hypercholesterolaemia from structure of LDL receptor module

Nature. 1997 Aug 14;388(6643):691-3. doi: 10.1038/41798.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Calcium / chemistry
  • Crystallography, X-Ray
  • Humans
  • Hypercholesterolemia / genetics*
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Protein Conformation
  • Receptors, LDL / chemistry*
  • Receptors, LDL / genetics


  • Receptors, LDL
  • Calcium

Associated data

  • PDB/1AJJ