GOF PCSK9-L108R in the prodomain rescues PCSK9-mediated degradation of LDLR-R410S via the extracellular pathway. HEK293 cells overexpressing LDLR-WT (WT) or LDLR-R410S (RS) were incubated for 18 h with conditioned media from HEK293 cells: no PCSK9 control-media (Cnt) or PCSK9-media (∼1.1 μg/ml), PCSK9-WT (PC9-WT), or GOF PCSK9-L108R (PC9-LR). A, total LDLR quantification by ELISA. B, FACS analyses of cell surface LDLR. Data are representative of four independent experiments. Bars are averages ± S.D. *, p < 0.05; **, p < 0.01 (t test).