Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia.
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.
Cunningham
David
D
Pfizer Inc., Eastern Point Road, Groton, Connecticut 06430, USA.
Danley
Dennis E
DE
Geoghegan
Kieran F
KF
Griffor
Matthew C
MC
Hawkins
Julie L
JL
Subashi
Timothy A
TA
Varghese
Alison H
AH
Ammirati
Mark J
MJ
Culp
Jeffrey S
JS
Hoth
Lise R
LR
Mansour
Mahmoud N
MN
McGrath
Katherine M
KM
Seddon
Andrew P
AP
Shenolikar
Shirish
S
Stutzman-Engwall
Kim J
KJ
Warren
Laurie C
LC
Xia
Donghui
D
Qiu
Xiayang
X
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*
D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases