PCSK9 Inhibitors
Cholesterol Lowering Drugs

Author: Gianpiero Pescarmona
Date: 06/06/2014



Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, is an enzyme that in humans is encoded by the PCSK9 gene. PSCK9, is inactive when it is first synthesized, because it has a section of peptide chains that blocks its activity; proprotein convertases remove that section to activate the enzyme. PCSK9 has medical significance because it acts in cholesterol homeostasis. Drugs that block PCSK9 can lower low-density lipoprotein cholesterol (LDL-C).

An Anti-PCSK9 Antibody Reduces LDL-Cholesterol On Top Of A Statin And Suppresses Hepatocyte SREBP-Regulated Genes , 2012


Your Favorite Gene Sigma"PCSK9":


When relevant for the function

  • Primary structure
  • Secondary structure
  • Tertiary structure
  • Quaternary structure

Protein Aminoacids Percentage

The 2 proteins have many similarities (Chart 2) but also significant differences:

  • LDLR high aspartate (high oxalacetate, high Krebs cycle rate?)
  • PCSK9 high alanine low aspartate (high pyruvate?)


mRNA synthesis
protein synthesis

post-translational modifications

Autocatalytic cleavage is required to transport it from the endoplasmic reticulum to the Golgi apparatus and for the secretion of the mature protein.

  • Localizes to the endoplasmic reticulum in the absence of LDLR
  • Colocalizes to the cell surface and to the endosomes/lysosomes in the presence of LDLR.

The sorting to the cell surface and endosomes is required in order to fully promote LDLR degradation.

In the rough endoplasmic reticulum (ER), the inactive form of proprotein convertase subtilisin kexin 9 (PCSK9) — the zymogen proPCSK9 (amino acids 31–692) —undergoes an intramolecular autocatalytic cleavage at its internal site (VFAQ152↓) to generate the prosegment (amino acids 31–152) and PCSK9 (amino acids 153–692) that remain tightly bound as a prosegment–PCSK9 complex28, 46. The enzymatically inactive tight binding complex of prosegment–PCSK9 exits the ER, traverses the Golgi and is constitutively secreted from the trans-Golgi network into the medium. If proPCSK9 cannot be processed (indicated by a red star), because of a heterozygous natural mutation (for example, Q152H) or owing to the presence of an inhibitor, it remains as a zymogen in the ER and binds the non-mutated wild-type sequence, thereby acting like a dominant negative mutant, and effectively preventing PCSK9 secretion. Upon reaching the trans-Golgi network, the wild-type prosegment–PCSK9 complex can either be sorted directly to lysosomes as a complex with the low-density lipoprotein receptor (LDLR) (intracellular pathway), or it is secreted and then internalized with the LDLR into clathrin-coated endosomes for lysosomal targeting and degradation, which requires the binding of the cytosolic adaptor protein autosomal recessive hypercholesterolaemia protein (ARH) (extracellular pathway). It is not yet clear whether the cell surface PCSK9 competes with apolipoprotein B (APOB) on the LDL particles for LDLR binding. In the absence of PCSK9, the endocytosed APOB–LDLR complex dissociates and the LDLR is recycled back to the cell surface. In the presence of PCSK9 and within the acidic milieu of endosomes the LDLR is not recycled, and (by a currently undefined mechanism) the PCSK9–LDLR tight binding complex is sent to lysosomes for degradation. (The biology and therapeutic targeting of the proprotein convertases, 2012)



cellular localization,
biological function

  • Enzymes
BRENDA - The Comprehensive Enzyme Information System"URL":
KEGG Pathways"URL":
Human Metabolome Database"URL":
  • Cell signaling and Ligand transport
  • Structural proteins


Statins treatment enhances PCSK9



alirocumab (Sanofi, Regeneron) 3 fold more effective than Ezetimibe in reducing LDL-cholesterol

2014-09-01T12:58:37 - Gianpiero Pescarmona

Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation. Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. Inhibits epithelial Na+ channel (ENaC)-mediated Na+ absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.

Monomer. Can self-associate to form dimers and higher multimers which may have increased LDLR degrading activity. The precursor protein but not the mature protein may form multimers. Interacts with APOB, VLDLR, LRP8/APOER2 and BACE1. The full length immature form (pro-PCSK9) interacts with SCNN1A, SCNN1B and SCNN1G. The pro-PCSK9 form (via C-terminal domain) interacts with LDLR


  • Binds VLDL and transports it into cells by endocytosis. In order to be internalized, the receptor-ligand complexes must first cluster into clathrin-coated pits. Binding to Reelin induces tyrosine phosphorylation of Dab1 and modulation of Tau phosphorylation By similarity.
    Subunit structure

Binds to the extracellular matrix protein Reelin RELN_HUMAN. Interacts with VLDLR. Interacts with SNX17 By similarity. Interacts with DAB1. Receptor for the minor-group human rhinoviruses (HRVs); binds protein VP1 through the second and third LDL-receptor class A domains. Interacts with PCSK9. Ref.9 Ref.10
Subcellular location

Membrane; Single-pass type I membrane protein. Membrane › clathrin-coated pit; Single-pass type I membrane protein.
Tissue specificity

Abundant in heart and skeletal muscle; also ovary and kidney; not in liver.
Post-translational modification

Ubiquitinated at Lys-839 by MYLIP leading to degradation. Ref.11
Involvement in disease

Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 1 (CAMRQ1) [MIM:224050]: A congenital, non-progressive cerebellar ataxia associated with disturbed equilibrium, delayed ambulation, mental retardation, cerebellar hypoplasia and mild cerebral gyral simplification. Additional features include short stature, strabismus, pes planus and, rarely, seizures.
Note: The disease is caused by mutations affecting the gene represented in this entry.
SCNNB_HUMAN Interacts with the full length immature form of PCSK9 (pro-PCSK9).

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