Formation of the covalently stablized α1-antitrypsin (α1-AT)-neutrophil elastase complex, the archetype of serpin-enzyme complexes, results in a structurally rearranged α1-AT molecule that possesses chemo-attractant activities, mediates an increase in synthesis of α1-AT by mononuclear phagocytes and hepatocytes, and is more rapidly cleared from the circulation than is the native α1-AT molecule. We have recently identified an abundant, high affinity cell surface receptor on human hepatoma HepG2 cells and human monocytes that binds α1-AT-elastase complexes, mediates endocytosis and lysosomal degradation of α1-AT-elastase complexes, and induces an increase in synthesis of α1-AT. We have referred to this receptor as the serpin-enzyme complex, or SEC, receptor because it also recognizes complexes of serpins antithrombin III, α1-antichymotrypsin, and C1 inhibitor with their cognate enzymes. In the current study, we show that a pentapeptide domain in the carboxyl terminal fragment of α1-AT (amino acids 370-374, FVFLM) is sufficient for binding to the SEC receptor. A synthetic analog of this pentapeptide (peptide 105C, FVYLI) blocks binding and internalization of α1-AT-125I-trypsin complexes by HepG2 cells. 125I-peptide 105C binds specifically and saturably to HepG2 cells, and its binding is blocked by α1-AT-trypsin or α1-AT-elastase complexes. Alterations of this sequence introduced into synthetic peptides (mutations, deletions, or scrambling) demonstrate that binding of the pentapeptide domain is sequence-specific. Comparisons with the sequences of other serpins in the corresponding region indicate that this pentapeptide neodomain is highly conserved.
|Number of pages||7|
|Journal||Journal of Biological Chemistry|
|State||Published - Sep 6 1991|