CHARACTERIZATION OF HIGH-AFFINITY BINDING BETWEEN LAMININ AND THE ACUTE-PHASE PROTEIN, SERUM AMYLOID-A

Serum amyloid A isoforms, apoSAA1 and apoSAA2, are acute-phase protein s of unknown function and can be precursors of amyloid AA peptides (AA ) found in animal and human amyloid deposits. These deposits are often a complication of chronic inflammatory disorders and are associated w ith a local disturbance in basement membrane (BM). In the course of tr ying to understand the pathogenesis of this disease laminin, a major B M glycoprotein, has been discovered to bind saturably, and with high a ffinity to murine acute-phase apoSAA. This interaction involves a sing le class of binding sites, which are ionic in nature, conformation-dep endent, and possibly involve sulfhydryls. Binding activity was signifi cantly enhanced by Zn2+, an effect possibly mediated through Cys-rich zinc finger-like sequences on laminin. Collagen type TV also bound apo SAA but with lower affinity. Unexpectedly, no binding was detected for perlecan, a BM proteoglycan previously implicated in AA fibrillogenes is, although a low affinity interaction cannot be excluded. Entactin, another BM protein that functions to cross-link the BM matrix and is n ormally complexed with laminin, could inhibit laminin-apoSAA binding s uggesting apoSAA does not bind to normal BM. Since laminin binds apoSA A with high affinity and has previously been shown to codeposit with A A amyloid fibrils, we postulate that laminin interacts with apoSAA and facilitates nucleation events leading to fibrillogenesis. This work a lso provides further support for the hypothesis that a disturbance in BM metabolism contributes to the genesis of amyloid. The specificity a nd avidity of the laminin-apoSAA interaction also implies that it may be a normal event occurring during the inflammatory process, which med iates one or more of the functions recently proposed for apoSAA.