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apolipoprotein

Function: - main constituent of lipoprotein - has serine proteinase activity - capable of autoproteolysis - inhibits tissue-type plasminogen activator 1 - may be a ligand for megalin/Gp 330 - binds to fibronectin & decorin Structure: - found in lipoprotein covalently linked to apo-B100 via a disulfide linkage - homologous with plasminogen - variable number of kringle domains (10-50) [3] - belongs to the peptidase S1 family, plasminogen subfamily - contains 1 peptidase S1 domain - N-glycosylated & O-glycosylated - the N-glycans are complex biantennary structures present in either a mono- or disialylated state - the O-glycans are mostly (80%) represented by monosialylated core type I structure, neuNAcalpha2-3galbeta1-3galNAc, with smaller amounts of disialylated & non-sialylated O-glycans Polymorphism: - variable number of kringle domains (3-43) [4] Pathology: - apo fragments accumulate in atherosclerotic lesions, where they may promote thrombogenesis - homology with plasminogen kringle domains IV & V is thought to underlie the atherogenicity of the protein, because the fragments are competing with plasminogen for fibrin/ fibrinogen binding Pharmacology: - olpasiran is a small interfering RNA that reduces apolipoprotein(a) synthesis in the liver [6] Notes: - known to be proteolytically cleaved, leading to the formation of the so-called mini-Lp - O-glycosylation may limit the extent of proteolytic fragmentation

General

apolipoprotein glycoprotein serine protease trypsin family

Properties

SIZE: MW = 400-800 kD COMPARTMENT: extracellular compartment MOTIF: kringle domain (38) N-glycosylation site (MANY) charge relay system MOTIF: aspartate residue histidine residue serine residue binding site FOR-BINDING-OF: lipid cysteine residue {C4057} S1 domain {4328-4546}

Database Correlations

OMIM 152200 UniProt P08519 PFAM correlations Entrez Gene 4018 Kegg hsa:4018

References

  1. Primary Hyperlipoproteinemias, Steiner & Shafrir (eds), McGraw Hill, NY, 1991, pg 28,53
  2. Entrez Gene :accession 4018
  3. Wikipedia: Lipoprotein(a) http://en.wikipedia.org/wiki/Lipoprotein(a)
  4. UniProt :accession P08519
  5. SHMPD; Singapore human mutation and polymorphism database http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename=APOA
  6. O'Donoghue ML, Rosenson RS, Gencer B et al Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease. N Engl J Med. 2022. Nov 6 PMID: 36342163 https://www.nejm.org/doi/full/10.1056/NEJMoa2211023

Component-of

lipoprotein ; Lp