title: Sorting an LDL receptor with bound PCSK9 to intracellular degradation.
abstract: OBJECTIVE
  This article reviews the mechanism by which the low density lipoprotein receptor (LDLR) that has bound proprotein convertase subtilisin/kexin type 9 (PCSK9), is rerouted to intracellular degradation instead of being recycled.
  
  
  METHODS
  A search of relevant published literature has been conducted.
  
  
  RESULTS
  PCSK9 binds to the LDLR at the cell surface. It is the catalytic domain of PCSK9 that binds to the epidermal growth factor repeat A of the LDLR. The LDLR:PCSK9 complex is internalized through clathrin-mediated endocytosis. Due to an additional electrostatic interaction at acidic pH between the C-terminal domain of PCSK9 and the ligand-binding domain of the LDLR, PCSK9 remains bound to the LDLR in the sorting endosome. As a consequence, the LDLR fails to adopt a closed conformation and is degraded instead of being recycled. The mechanism for the failure of the LDLR to recycle appears to involve ectodomain cleavage of the extended LDLR by a cysteine cathepsin in the sorting endosome. The cleaved LDLR ectodomain will be confined to the vesicular part of the sorting endosome for degradation in the endosomal/lysosomal tract.
  
  
  CONCLUSIONS
  Ectodomain cleavage of an LDLR with bound PCSK9 in the sorting endosome disrupts the normal recycling of the LDLR.
authors.affiliation: Unit for Cardiac and Cardiovascular Genetics, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. Electronic address: trond.leren@rikshospitalet.no.
authors.forename: Trond P
authors.initials: TP
authors.lastname: Leren
mesh_terms: D000818:Animals; D002403:Cathepsins / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003545:Cysteine / Q000737:chemistry / Q000235:genetics; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D008247:Lysosomes / Q000378:metabolism; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000378:metabolism*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011973:Receptors, LDL / Q000097:blood* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*
chemical_list: D008024:Ligands; D011973:Receptors, LDL; D002403:Cathepsins; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D003545:Cysteine
keywords: Cathepsin; Degradation; Endosome; LDL receptor; PCSK9