Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia.

Journal Article (Journal Article)

Proprotein convertase subtilisin kexin type 9 (PCSK9) lowers the abundance of surface low-density lipoprotein (LDL) receptor through an undefined mechanism. The structure of human PCSK9 shows the subtilisin-like catalytic site blocked by the prodomain in a noncovalent complex and inaccessible to exogenous ligands, and that the C-terminal domain has a novel fold. Biosensor studies show that PCSK9 binds the extracellular domain of LDL receptor with K(d) = 170 nM at the neutral pH of plasma, but with a K(d) as low as 1 nM at the acidic pH of endosomes. The D374Y gain-of-function mutant, associated with hypercholesterolemia and early-onset cardiovascular disease, binds the receptor 25 times more tightly than wild-type PCSK9 at neutral pH and remains exclusively in a high-affinity complex at the acidic pH. PCSK9 may diminish LDL receptors by a mechanism that requires direct binding but not necessarily receptor proteolysis.

Full Text

Duke Authors

Cited Authors

  • Cunningham, D; Danley, DE; Geoghegan, KF; Griffor, MC; Hawkins, JL; Subashi, TA; Varghese, AH; Ammirati, MJ; Culp, JS; Hoth, LR; Mansour, MN; McGrath, KM; Seddon, AP; Shenolikar, S; Stutzman-Engwall, KJ; Warren, LC; Xia, D; Qiu, X

Published Date

  • May 2007

Published In

Volume / Issue

  • 14 / 5

Start / End Page

  • 413 - 419

PubMed ID

  • 17435765

International Standard Serial Number (ISSN)

  • 1545-9993

Digital Object Identifier (DOI)

  • 10.1038/nsmb1235


  • eng

Conference Location

  • United States