Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia - PubMed (original) (raw)
doi: 10.1038/nsmb1235. Epub 2007 Apr 15.
Dennis E Danley, Kieran F Geoghegan, Matthew C Griffor, Julie L Hawkins, Timothy A Subashi, Alison H Varghese, Mark J Ammirati, Jeffrey S Culp, Lise R Hoth, Mahmoud N Mansour, Katherine M McGrath, Andrew P Seddon, Shirish Shenolikar, Kim J Stutzman-Engwall, Laurie C Warren, Donghui Xia, Xiayang Qiu
Affiliations
- PMID: 17435765
- DOI: 10.1038/nsmb1235
Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia
David Cunningham et al. Nat Struct Mol Biol. 2007 May.
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.
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