Proprotein Convertase Subtilisin/Kexin 6 in Cardiovascular Biology and Disease

Figures

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  Figure 1. Schematic presentation of human PCSK6 domains. Human PCSK6 consists of a signal peptide (Signal), a pro-domain, a subtilisin-like catalytic domain, a P or Homo B domain, and a C-terminal cysteine-rich domain. In the catalytic domain, the conserved active sites, Asp (D), His (H), and Ser (S), are at positions 205, 246, and 420, respectively. Three predicted N-glycosylation sites (Y shaped symbols) are at positions 259, 914, and 932, respectively. Two autoactivation cleavage sites are at Arg (R) 117 (open arrowhead) (second cleavage) and R149 (red arrowhead) (first cleavage).

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  Figure 2. PCSK6 intracellular trafficking and autoactivation. PCSK6 is synthesized as a one-chain zymogen. The signal peptide is removed by signal peptidase in the ER (not shown). The pro-domain (white), the catalytic domain (blue), the P/Homo B domain (gray), and the C-terminal cysteine-rich domain (black) are shown. Within the ER, first autocleavage occurs between the pro-domain and the catalytic domain (red arrowhead). The cleaved pro-domain remains attached, acts as an inhibitor of PCSK6, and facilitates PCSK6 folding and ER exiting. Upon secretion, a second autocleavage occurs within the pro-domain (open arrowhead), which disassociates the pro-domain, converting PCSK6 to an active enzyme.

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  Figure 3. Role of PCSK6 in cardiovascular development and pathophysiology. PCSK6 plays a key role in atrial septum formation during embryogenesis. In adult stages, PCSK6 regulates lipoprotein metabolism and blood pressure by inactivating endothelial lipase and activating corin, respectively. PCSK6 participates in vascular remodeling and cardiac repair under pathological conditions such as atherosclerosis and acute MI. In aged hearts, PCKS6 prevents senescence in cardiomyocytes by reducing ER stress.