Platelet activation by the apoB/E receptor-binding domain of LDL.
Low density lipoprotein (LDL) increases the sensitivity of human platelets for agonists by activating p38MAPK. Antibody 4G3 disturbs apoB100 binding to the classical apoB/E receptor and inhibits LDL-induced p38MAPK activation, whereas an antibody against a distal domain on apoB 100 has no effect. Peptide RLTRKRGLKLA mimics the binding domain of apoB 100 called the B-site and activates platelet p38MAPK. Activation by B-site peptide is dose-dependent, transient and followed by desensitization, in accordance with receptor-mediated signalling. A scrambled peptide and a partially homologous peptide RKLRKRLLRDA mimicking the apoB/E receptor binding site of apoE in high density lipoprotein (HDL) also activate p38MAPK albeit 40% weaker, but an uncharged peptide lacks p38MAPK activating capacity. LDL and B-site peptide bind to the same binding sites and initiate similar signalling to p38MAPK and cytosolic phospholipase A2. Thus, LDL and to a lesser extent HDL activate platelets via specific domains in the protein moiety that recognize receptors of the LDL receptor family.
Relou
A M
AM
Department of Haematology, University Medical Center Utrecht, The Netherlands. i.relou@lab.azu.nl
Gorter
G
G
van Rijn
H J M
HJ
Akkerman
J W N
JW
D000595:Amino Acid Sequence; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D001057:Apolipoproteins E / Q000494:pharmacology; D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000097:blood; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation; D015539:Platelet Activation / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017434:Protein Structure, Tertiary; D018110:Receptors, Lipoprotein / Q000187:drug effects / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D001057:Apolipoproteins E; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D010446:Peptide Fragments; D018110:Receptors, Lipoprotein; C032531:apolipoprotein B,E receptor; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases