Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia
| Autor: | Laurie C. Warren, Donghui Xia, Alison H. Varghese, Mark Ammirati, David Cunningham, Kieran F. Geoghegan, Timothy A. Subashi, Dennis E. Danley, Julie Jia Li Hawkins, Mahmoud N. Mansour, Katherine M McGrath, Shirish Shenolikar, Xiayang Qiu, Lise R. Hoth, Matthew C. Griffor, Kim Jonelle Stutzman-Engwall, Andrew P. Seddon, Jeffrey S. Culp |
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| Rok vydání: | 2007 |
| Předmět: |
Binding Sites
Chemistry Endosome Protein Conformation PCSK9 Hypercholesterolemia Serine Endopeptidases Subtilisin Mutation Missense Plasma protein binding Hydrogen-Ion Concentration Proprotein convertase Biochemistry Receptors LDL Structural Biology LDL receptor Kexin Humans Proprotein Convertases Binding site Proprotein Convertase 9 Molecular Biology Protein Binding |
| Zdroj: | Nature structuralmolecular biology. 14(5) |
| ISSN: | 1545-9993 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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