Key result
PCSK9 point mutations Q152H and Q152N prevent the formation of mature PCSK9 by hindering folding, reducing autoproteolysis, and destabilizing the protein, preventing LDL receptor binding.
PCSK9 loss-of-function mutations Q152H and Q152N reduce LDLc by hindering protein folding, autoproteolysis, and LDLr binding, providing mechanistic insight into their lipid-lowering effects.
Rare PCSK9 mutations may confer LDL-lowering effects; leaves open population-level validation and clinical translation.
Circulating low-density lipoprotein cholesterol (LDLc) is regulated by membrane-bound LDL receptor (LDLr). Upon LDLc and LDLr interaction the complex is internalized by the cell, leading to LDLc degradation and LDLr recycling back to the cell surface. The proprotein convertase subtilisin/kexin type 9 (PCSK9) protein regulates this cycling. PCSK9 is secreted from the cell and binds LDLr. When the complex is internalized, PCSK9 prevents LDLr from shuttling back to the surface and instead targets it for degradation. PCSK9 is a serine protease expressed as a zymogen that undergoes autoproteolysis, though the two resulting protein domains remain stably associated as a heterodimer. This PCSK9 autoprocessing is required for the protein to be secreted from the cell. To date, direct analysis of PCSK9 autoprocessing has proven challenging, as no catalytically active zymogen has been isolated. A PCSK9 loss-of-function point mutation (Q152H) that reduces LDLc levels two-fold was identified in a patient population. LDLc reduction was attributed to a lack of PCSK9(Q152H) autoprocessing preventing secretion of the protein. We have isolated a zymogen form of PCSK9, PCSK9(Q152H), and a related mutation (Q152N), that can undergo slow autoproteolysis. We show that the point mutation prevents the formation of the mature form of PCSK9 by hindering folding, reducing the rate of autoproteolysis, and destabilizing the heterodimeric form of the protein. In addition, we show that the zymogen form of PCSK9 adopts a structure that is distinct from the processed form and is unable to bind a mimetic peptide based on the EGF-A domain of the LDLr.
No takes yet. Share an insight, caveat, or question.
Garvie et al. (2016) studied this question. PCSK9 point mutations (Q152H and Q152N) was evaluated on PCSK9 autoprocessing, folding, and LDL receptor interaction. PCSK9 point mutations Q152H and Q152N prevent the formation of mature PCSK9 by hindering folding, reducing autoproteolysis, and destabilizing the protein, preventing LDL receptor binding.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: