page_title: PCSK9
section_title: Protein
hierarchical_section_title: PCSK9 / Structure / Protein
caption_attribution_description: বাংলা: 2p4e কোডসহ নিবন্ধিত প্রোটিনের আণবিক গঠনের কার্টুন উপস্থাপনা। English: Cartoon representation of the molecular structure of protein registered with 2p4e code. Deutsch: Grafik des Molekularstruktur von jenem Protein, das mit 2p4e code registriert ist. Plattdüütsch: Grafik, de de Molekularstruktur von dat Protein wiest, dat mit’n Kood 2p4e registreert is.
context_page_description: Proprotein convertase subtilisin/kexin type 9 is an enzyme encoded by the PCSK9 gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes are found across many species. As with many proteins, PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme. The PCSK9 gene also contains one of 27 loci associated with increased risk of coronary artery disease.
  PCSK9 is ubiquitously expressed in many tissues and cell types. PCSK9 binds to the receptor for low-density lipoprotein particles, which typically transport 3,000 to 6,000 fat molecules per particle, within extracellular fluid. The LDL receptor, on liver and other cell membranes, binds and initiates ingestion of LDL-particles from extracellular fluid into cells, thus reducing LDL particle concentrations. If PCSK9 is blocked, more LDLRs are recycled and are present on the surface of cells to remove LDL-particles from the extracellular fluid. Therefore, blocking PCSK9 can lower blood LDL-particle concentrations.
context_section_description: PCSK9 is a member of the peptidase S8 family.
  The solved structure of PCSK9 reveals four major components in the pre-processed protein: the signal peptide (residues 1-30); the N-terminal prodomain (residues 31-152); the catalytic domain (residues 153-425); and the C-terminal domain (residues 426-692), which is further divided into three modules. The N-terminal prodomain has a flexible crystal structure and is responsible for regulating PCSK9 function by interacting with and blocking the catalytic domain, which otherwise binds the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR. While previous studies indicated that the C-terminal domain was uninvolved in binding LDLR, a recent study by Du et al. demonstrated that the C-terminal domain does bind LDLR. The secretion of PCSK9 is largely dependent on the autocleavage of the signal peptide and N-terminal prodomain, though the N-terminal prodomain retains its association with the catalytic domain. In particular, residues 61-70 in the N-terminal prodomain are crucial for its autoprocessing.
caption: 2p4e: Crystal structure of PCSK9[32]
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