PCSK9 protein structure and selected mutations. PCSK9 protein includes a pro-domain (Pro) that is self-cleaved during secretion and remains tightly associated, a catalytic domain, and a C-terminal domain. Activating mutations such as D374Y cause increased affinity for LDLR. Inactivating mutations such as Y142X and C679X block self-cleavage and secretion of the protein. The R46L mutation results in decreased circulating levels of PCSK9 protein, although the mechanism is not completely understood.