Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted protein that 
binds to the epidermal growth factor-like-A domain of the low density 
lipoprotein receptor (LDLR) and mediates LDLR degradation in liver. 
Gain-of-function mutations in PCSK9 are associated with autosomal dominant 
hypercholesterolemia in humans. Size-exclusion chromatography of human plasma 
has shown PCSK9 to be partly associated with undefined high molecular weight 
complexes within the LDL size range. We used density gradient centrifugation to 
isolate LDL in plasma pooled from 5 normolipidemic subjects and report that >40% 
of total PCSK9 was associated with LDL. Binding of fluorophore-labeled 
recombinant PCSK9 to isolated LDL in vitro was saturable with a K(D) ∼ 325 nM. 
This interaction was competed >95% by excess unlabeled PCSK9, and competition 
binding curves were consistent with a one-site binding model. An N-terminal 
region of the PCSK9 prodomain (amino acids 31-52) was required for binding to 
LDL in vitro. LDL dose-dependently inhibited binding and degradation of cell 
surface LDLRs by exogenous PCSK9 in HuH7 cells. LDL also inhibited PCSK9 binding 
to mutant LDLRs defective at binding LDL. These data suggest that association of 
PCSK9 with LDL particles in plasma lowers the ability of PCSK9 to bind to cell 
surface LDLRs, thereby blunting PCSK9-mediated LDLR degradation.