THE STRUCTURAL BASIS OF GERMLINE-ENCODED V(H)3 IMMUNOGLOBULIN BINDINGTO STAPHYLOCOCCAL PROTEIN-A

The ability of human V(H)3 immunoglobulins (Ig) to bind to staphylococ cal protein A (SPA) via their Fab region is analogous to the binding o f bacterial superantigens to T cell receptors. The present report esta blishes the structural basis for the interaction of SPA and V(H)3 Ig. We have studied a panel of 27 human monoclonal IgM that were derived f rom fetal B lymphocytes. As such, these IgM were expected to be encode d by unmutated germline genes. Binding to SPA in ELISA occurred with 1 5 of 15 V(H)3 IgM, but none of 12 IgM from the V(H)1, V(H)4, V(H)5, or V(H)6 families. The V(H) sequences of the 27 IgM were derived from 20 distinct V(H) elements, including 11 from the V(H)3 family. Use of D, J(H), and C(L) genes was similar among V(H)3 and non-V(H)3 IgM. A com parison of the corresponding V(H) protein sequences, and those of prev iously studied IgM, identified a probable site for SPA binding that in cludes V(H)3 residues in framework region 3 (FR3), and perhaps FR1 and 3' complementary determining region 2. The results thus demonstrate t hat among human IgM, specificity for SPA is encoded by at least 11 dif ferent V(H)3 germline genes. Furthermore, like the T cell superantigen s, SPA likely binds to residues in the V(H) framework region, outside the classical antigen-binding site of the hypervariable loops.