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J Lipid Res. 2011 Oct;52(10):1787-94. doi: 10.1194/jlr.M018093. Epub 2011 Jul 19.

Role of the C-terminal domain of PCSK9 in degradation of the LDL receptors.

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  • 1Unit for Cardiac and Cardiovascular Genetics, Department of Medical Genetics, Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway.


Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low density lipoprotein receptor (LDLR) at the cell surface and disrupts the normal recycling of the LDLR. In this study, we investigated the role of the C-terminal domain for the activity of PCSK9. Experiments in which conserved residues and histidines on the surface of the C-terminal domain were mutated indicated that no specific residues of the C-terminal domain, apart from those responsible for maintaining the overall structure, are required for the activity of PCSK9. Rather, the net charge of the C-terminal domain is important. The more positively charged the C-terminal domain, the higher the activity toward the LDLR. Moreover, replacement of the C-terminal domain with an unrelated protein of comparable size led to significant activity of the chimeric protein. We conclude that the role of the evolutionary, poorly conserved C-terminal domain for the activity of PCSK9 reflects its overall positive charge and size and not the presence of specific residues involved in protein-protein interactions.

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