Formation of the covalently stabilized complex of α1-antitrypsin (α1-AT) with neutrophil elastase, the archetype of serine proteinase inhibitor serpin-enzyme complexes, is associated with structural rearrangement of the α1-AT molecule and hydrolysis of a reactive-site peptide bond. An ≈ 4-kDa carboxyl-terminal cleavage fragment is generated. α1-AT-elastase complexes are biologically active, possessing chemotactic activity and mediating increases in expression of the α1-AT gene in human monocytes and macrophages. This suggested that structural rearrangement of the α1-AT molecule, during formation of a complex with elastase, exposes a domain that is recognized by a specific cell surface receptor or receptors. To test this hypothesis, the known three-dimensional structure of α1,-AT and comparisons of the primary structures of the serpins were used to select a potentially exteriorly exposed and highly conserved region in the complexed form of α1-AT as a candidate ligand (carboxyl-terminal fragment, amino acids 359-374). We show here that synthetic peptides based on the sequence of this region bind specifically and anturably to human hepatoma cells and human monocytes (Kd = 4.0 × 10-8 M, 4.5 × 105 plasma membrane receptors per cell) and mediate increases in synthesis of α1-AT. Binding of peptide 105Y (Ser-Ile-Pro-Pro-Glu-Val-Lys-Phe-Asn-Lys-Pro-Phe-Val-Tyr-Leu-Ile) is blocked by α1-AT-elastase complexes, antithrombin III (AT Ill)-thrombin complexes, α1-antichymotrypsin (α1-ACT)-cathepsin G complexes, and, to a ser extent, complement component C1 inhibitor-C1s complexes, but not by the corresponding native proteins. Binding of peptide 105Y is also blocked by peptides with sequence corresponding to carboxyl-terminal fragments of the serpins AT III and α1-ACT, but not by peptides having the sequence of the extreme amino terminus of α1-AT. The results also show that peptide 105Y inhibits binding of 125I-labeled α1-AT-aducstase complexes. Thus, these studies demonstrate an abundant, relatively high-affinity cell surface receptor which recognizes serpin-enzyme complexes (SEC receptor). This receptor is capable of modulating the production of at least one of the serpins, α1-AT. Since the ligand specificity is similar to that previously described for in vivo clearance of serpin-enzyme complexes, the SEC receptor may also be involved in the clearance of certain serpin-enzyme complexes.
|Original language||English (US)|
|Number of pages||5|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - 1990|
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