A transient amphipathic helix in the prodomain of PCSK9 facilitates binding to low-density lipoprotein particles
Samantha K. Sarkar, Alexander C. Y. Foo, Angela Matyas, Ikhuosho Asikhia, Tanja Kosenko, Natalie K. Goto, Ariela Vergara‐Jaque, Thomas A. Lagace
Abstract
mutations associated with familial hypercholesterolemia (FH) and clustered at the predicted interdomain interface (R469W, R496W, and F515L) inhibited LDL binding, which was completely abolished in the case of the R496W variant. These findings shed light on allosteric conformational changes in PCSK9 required for high-affinity binding to LDL particles. Moreover, the initial identification of FH-associated mutations that diminish PCSK9's ability to bind LDL reported here supports the notion that PCSK9-LDL association in the circulation inhibits PCSK9 activity.
Topics & Concepts
Proprotein convertaseKexinPCSK9LDL receptorFamilial hypercholesterolemiaEndosomeChemistryBiochemistryBiophysicsLow-density lipoproteinProprotein ConvertasesLipoproteinReceptorCholesterolBiologyLipoproteins and Cardiovascular HealthChronic Lymphocytic Leukemia Research