Role of the C-terminal domain of PCSK9 in degradation of the LDL receptors

J Lipid Res. 2011 Oct;52(10):1787-94. doi: 10.1194/jlr.M018093. Epub 2011 Jul 19.


Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low density lipoprotein receptor (LDLR) at the cell surface and disrupts the normal recycling of the LDLR. In this study, we investigated the role of the C-terminal domain for the activity of PCSK9. Experiments in which conserved residues and histidines on the surface of the C-terminal domain were mutated indicated that no specific residues of the C-terminal domain, apart from those responsible for maintaining the overall structure, are required for the activity of PCSK9. Rather, the net charge of the C-terminal domain is important. The more positively charged the C-terminal domain, the higher the activity toward the LDLR. Moreover, replacement of the C-terminal domain with an unrelated protein of comparable size led to significant activity of the chimeric protein. We conclude that the role of the evolutionary, poorly conserved C-terminal domain for the activity of PCSK9 reflects its overall positive charge and size and not the presence of specific residues involved in protein-protein interactions.

MeSH terms

  • Alanine / chemistry
  • Alanine / metabolism
  • Amino Acid Sequence
  • Endosomes / chemistry
  • Endosomes / metabolism*
  • Hep G2 Cells
  • Histidine / chemistry
  • Histidine / metabolism
  • Humans
  • Molecular Sequence Data
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Protein Binding
  • Receptors, LDL / chemistry
  • Receptors, LDL / metabolism*
  • Serine Endopeptidases / chemistry*
  • Serine Endopeptidases / metabolism*
  • Tumor Cells, Cultured


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