title: Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia.
abstract: 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.
authors: Pfizer Inc., Eastern Point Road, Groton, Connecticut 06430, USA.
authors: David
authors: D
authors: Cunningham
authors: Dennis E
authors: DE
authors: Danley
authors: Kieran F
authors: KF
authors: Geoghegan
authors: Matthew C
authors: MC
authors: Griffor
authors: Julie L
authors: JL
authors: Hawkins
authors: Timothy A
authors: TA
authors: Subashi
authors: Alison H
authors: AH
authors: Varghese
authors: Mark J
authors: MJ
authors: Ammirati
authors: Jeffrey S
authors: JS
authors: Culp
authors: Lise R
authors: LR
authors: Hoth
authors: Mahmoud N
authors: MN
authors: Mansour
authors: Katherine M
authors: KM
authors: McGrath
authors: Andrew P
authors: AP
authors: Seddon
authors: Shirish
authors: S
authors: Shenolikar
authors: Kim J
authors: KJ
authors: Stutzman-Engwall
authors: Laurie C
authors: LC
authors: Warren
authors: Donghui
authors: D
authors: Xia
authors: Xiayang
authors: X
authors: Qiu
mesh_terms: D001665:Binding Sites; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006937:Hypercholesterolemia / Q000209:etiology / Q000235:genetics*; D020125:Mutation, Missense / Q000502:physiology*; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011485:Protein Binding / Q000235:genetics; D011487:Protein Conformation; D011973:Receptors, LDL / Q000378:metabolism; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases