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M12 protein from Streptococcus pyogenes is a receptor for immunoglobulin G3 and human albumin
1Department of Microbiology, University of Minnesota, Minneapolis 55455.
Abstract:
We previously showed that M12 protein from opacity factor-negative Streptococcus pyogenes (group A streptococci) CS24 is responsible for immunoglobulin G3 (IgG3) binding activity. Here, we report that this M protein binds human serum albumin (HSA). Deletion analysis showed that the C repeats are sufficient for binding HSA, although upstream regions may be required for optimal binding. Like protein G, IgG3 and HSA bind to independent domains in the M protein. Experiments showed that bound IgG3 did not inhibit HSA binding to the M protein. The interaction between M12 protein and HSA is specific. M12 protein does not bind chicken egg and bovine serum albumins. Alignments of C1 and C2 repeats of M12 protein to sequences at the carboxy termini of other M proteins and Ig receptors revealed highly homologous sequences in the FcRV, M5, M6, ML2.1, and M57 proteins, suggesting that all could bind HSA. As predicted from the alignment, M5 protein and M6+ streptococci bound HSA, whereas an isogenic M6- mutant did not bind HSA. Furthermore, M2 protein from an opacity factor-positive strain also bound HSA.
Insights
Streptococcus pyogenes M12 protein binds human serum albumin (HSA) via its C repeats, independent of immunoglobulin G3 (IgG3) binding. This interaction is specific, suggesting other M proteins may also bind HSA.
Area of Science:
- Microbiology
- Immunology
- Protein Biochemistry
Background:
- Streptococcus pyogenes M proteins are key virulence factors.
- M12 protein was previously identified as responsible for immunoglobulin G3 (IgG3) binding.
- The specific binding targets and domains of M proteins are crucial for understanding streptococcal pathogenesis.
Purpose of the Study:
- To investigate the binding activity of M12 protein beyond IgG3.
- To identify the specific domain within M12 protein responsible for human serum albumin (HSA) binding.
- To explore the potential of other M proteins to bind HSA.
Main Methods:
- Deletion analysis of M12 protein to map binding domains.
- Binding assays using purified M12 protein and human serum albumin (HSA).
- Sequence homology analysis of M protein domains with known Ig receptors and other M proteins.
- Testing of other M proteins (M5, M6, M2) and streptococcal strains for HSA binding.
Main Results:
- M12 protein specifically binds human serum albumin (HSA).
- The C repeats of M12 protein are sufficient for HSA binding, with potential contribution from upstream regions.
- IgG3 and HSA bind to distinct domains on M12 protein, and their binding is independent.
- M12 protein does not bind heterologous albumins (chicken egg, bovine serum albumin).
- Sequence homology suggests that M5, M6, and M2 proteins also bind HSA, which was experimentally confirmed for M5 and M2 proteins.
Conclusions:
- The M12 protein of Streptococcus pyogenes possesses dual specificity, binding both IgG3 and HSA.
- HSA binding is mediated by the C repeats of M12 protein, indicating a conserved binding mechanism across different M proteins.
- The findings suggest a broader role for M proteins in host immune evasion and nutrient acquisition through albumin binding.