Molecular basis of PCSK9 function.
The LDL receptor (LDLr) inhibitor Proprotein Convertase Subtilisin Kexin type 9 (PCSK9) has emerged as a genetically validated target for lowering plasma LDL cholesterol levels. In 2007, PCSK9 was found to act as a chaperone that binds the LDLr, thereby targeting it for lysosomal degradation. The enzymatic activity of PCSK9 is not involved in that process, but rather permits proper intramolecular processing of PCSK9. This was demonstrated by both site directed mutagenesis and independent reports of the PCSK9 crystal structure. These reports also elucidated the mode of action of several naturally occurring mutants of PCSK9 associated with hyper- or hypocholesterolemia. The present review summarizes studies published or in print before May 2008 investigating the functional significance of PCSK9 and its promising aspects as a prognostic tool and a drug target.
Lambert
Gilles
G
The Heart Research Institute, Camperdown, NSW 2050, Australia. lambertg@hri.org.au
Charlton
Francesca
F
Rye
Kerry-Anne
KA
Piper
Derek E
DE
D000818:Animals; D050197:Atherosclerosis / Q000175:diagnosis / Q000473:pathology; D018360:Crystallography, X-Ray / Q000379:methods; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics; D008247:Lysosomes / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D011379:Prognosis; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011973:Receptors, LDL / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics* / Q000502:physiology*
D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases