Secreted PCSK9 promotes LDL receptor degradation independently of proteolytic activity
2007
PCSK9(
proprotein convertase
subtilisin/
kexin9) is a secreted
serine proteasethat regulates cholesterol homoeostasis by inducing post-translational degradation of hepatic LDL-R [LDL (low-density lipoprotein) receptor]. Intramolecular autocatalytic processing of the
PCSK9
zymogenin the endoplasmic reticulum results in a tightly associated complex between the prodomain and the catalytic domain. Although the autocatalytic processing event is required for proper secretion of
PCSK9, the requirement of proteolytic activity in the regulation of LDL-R is currently unknown. Co-expression of the prodomain and the catalytic domain in trans allowed for production of a catalytically inactive secreted form of
PCSK9. This catalytically inactive
PCSK9was characterized and shown to be functionally equivalent to the wild-type protein in lowering cellular LDL uptake and LDL-R levels. These findings suggest that, apart from autocatalytic processing, the protease activity of
PCSK9is not necessary for LDL-R regulation.
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