In this study we localized more precisely the salivary glycoprotein-interacting and the human immunoglobulin G (hIgG)-cross-reacting domains on the SR molecule, an antigen I/Il-related protein from S. mutans serotype f. Mapping of the SR molecule with polypeptides expressed by subclones covering the entire molecule and with synthetic peptides demonstrates that the salivary glycoprotein-binding domain is located in the N-terminal alanine-rich repeats of the SR molecule. In order to investigate the degree of conservation of both regions in various oral streptococci, we tested the reactivity of 8 representative strains of the mutans group and 11 nonmutans oral Streptococcus strains (S. anginosus, S. milleri, S. consteUlatus, S. intermedius, S. mitis, S. sanguis, S. gordonii, S. salivarius, and S. mitis strains) with antipeptide antibodies in a whole-cell enzyme linked immunosorbent assay together with colony hybridization analysis using DNA probes designed to map these two regions. All the mutans group strains except S. rattus and the 11 nonmutans streptococcal strains showed a high conservation of the C-terminal part of the SR molecule, especially the hIgG-cross-reacting domain, and less homology for the N-terminal salivary glycoprotein-binding region. Almost all of the sera from patients with rheumatic disease reacted strongly with SR from S. mutans serotype f, PI from S. mutans serotype c, and four peptides located in the hIgG-cross-reacting region and not with peptides located at the C and N termini and in the proline-rich repeats. These results confirm that epitopes located within this region are immunogenic in humans and could lead to the synthesis of natural anti-IgG antibodies.