Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH

EMBO Rep. 2011 Dec 1;12(12):1300-5. doi: 10.1038/embor.2011.205.

Abstract

The protein PCSK9 (proprotein convertase subtilisin/kexin type 9) is a key regulator of low-density lipoprotein receptor (LDLR) levels and cardiovascular health. We have determined the crystal structure of LDLR bound to PCSK9 at neutral pH. The structure shows LDLR in a new extended conformation. The PCSK9 C-terminal domain is solvent exposed, enabling cofactor binding, whereas the catalytic domain and prodomain interact with LDLR epidermal growth factor(A) and β-propeller domains, respectively. Thus, PCSK9 seems to hold LDLR in an extended conformation and to interfere with conformational rearrangements required for LDLR recycling.

MeSH terms

  • Down-Regulation
  • Humans
  • Hydrogen-Ion Concentration
  • Models, Molecular
  • Proprotein Convertase 9
  • Proprotein Convertases / chemistry*
  • Proprotein Convertases / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Proteolysis
  • Receptors, LDL / chemistry*
  • Receptors, LDL / metabolism*
  • Serine Endopeptidases / chemistry*
  • Serine Endopeptidases / metabolism
  • Surface Plasmon Resonance

Substances

  • Receptors, LDL
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases