Identification and characterization of new gain-of-function mutations in the PCSK9 gene responsible for autosomal dominant hypercholesterolemia

Amyloid Precursor-like Protein 2 and Sortilin Do Not Regulate the PCSK9 Convertase-mediated Low Density Lipoprotein Receptor Degradation but Interact with Each Other

“…An alternative hypothesis postulates that, upon extracellular PCSK9 binding to the cell surface LDLR, the endocytosed membrane-bound PCSK9-LDLR complex is exposed to sheddase(s) that release the LDLR from the membrane (59), and accelerate its degradation. Whether the C-terminal domain of PCSK9, which is essential for LDLR degradation, acts through reinforcing the PCSK9-LDLR interaction (60,61), rather than through binding a third partner, remains to be proven (20 -22).…”

Induction of Sustained Hypercholesterolemia by Single Adeno-Associated Virus–Mediated Gene Transfer of Mutant hPCSK9

“…[9][10][11] Mice deficient for PCSK9 protein have low plasma LDL cholesterol levels and are protected against atherosclerosis development 12 ; in contrast, gain-of-function PCSK9 mutants 13 have hypercholesterolemia and accelerated atherosclerosis generation. [14][15][16] The most severe mutation described in PCSK9, identified in 2 populations, 10,17 results in cholesterol levels above 500 mg/dL. The mutation, an amino-acid substitution of Asp374 by Tyr (D374Y), increases the affinity of PCSK9 for the LDLR by ≥10-fold.…”

Pcsk9

“…6,7,15,16 After the discovery of PCSK9 and its relationship to circulating levels of LDL-cholesterol (LDL-C), 12,14 a race was sparked around the world to find not only new gain-of-function (GOF) mutations causing hypercholesterolemia 14,17 but also loss-of-function (LOF) mutations compatible with hypocholesterolemia. 18,19 The highly active Anglo-Saxon D374Y PCSK9 variant is the most remarkable GOF mutation,…”

“…One exception is the predicted weak hydrophobic interaction of Leu 626 of the β-propeller domain of the LDLR with Leu 108 of the prosegment of PCSK9, 41 which was also deduced from a GOF L108R PCSK9 mutant that possibly strengthens this interaction by favoring the electrostatic binding of Glu 605 of the LDLR to the mutant Arg 108 of PCSK9. 17 Nevertheless, because the cytosolic tail of the LDLR is not necessary for the sorting of the [PCSK9≡LDLR] complex to lysosomes, 44,55 this suggests that another protein must bind the luminal CHRD domain and that such protein X would also have a transmembrane domain and cytosolic tail linking motor proteins in the cytosol to direct the complex to lysosomes (Figure 1). 44 In that context, a recent report proposed that the amyloid precursor-like protein-2 (APLP-2) can bind the CHRD at the surface of cells and in endosomes, and that this [LDLR≡PCSK9≡APLP-2] tripartite complex is then targeted to lysosomes (Figure 2), 56 by a still undefined mechanism.…”