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Membrane cofactor protein (CD46) is a keratinocyte receptor for the M protein of the group A streptococcus
N Okada1, M K Liszewski, J P Atkinson
1Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110-1093, USA.
Abstract:
The pathogenic Gram-positive bacterium Streptococcus pyogenes (group A streptococcus) is the causative agent of numerous suppurative diseases of human skin. The M protein of S. pyogenes mediates the adherence of the bacterium to keratinocytes, the most numerous cell type in the epidermis. In this study, we have constructed and analyzed a series of mutant M proteins and have shown that the C repeat domain of the M molecule is responsible for cell recognition. The binding of factor H, a serum regulator of complement activation, to the C repeat region of M protein blocked bacterial adherence. Factor H is a member of a large family of complement regulatory proteins that share a homologous structural motif termed the short consensus repeat. Membrane cofactor protein (MCP), or CD46, is a short consensus repeat-containing protein found on the surface of keratinocytes, and purified MCP could competitively inhibit the adherence of S. pyogenes to these cells. Furthermore, the M protein was found to bind directly to MCP, whereas mutant M proteins that lacked the C repeat domain did not bind MCP, suggesting that recognition of MCP plays an important role in the ability of the streptococcus to adhere to keratinocytes.
Insights
Streptococcus pyogenes uses its M protein's C repeat domain to attach to skin cells. Blocking this interaction with factor H or membrane cofactor protein (MCP) inhibits bacterial adherence, revealing a key mechanism for skin infections.
Area of Science:
- Microbiology
- Immunology
- Dermatology
Background:
- * Streptococcus pyogenes (group A streptococcus) causes human skin infections.
- * M protein facilitates bacterial adherence to keratinocytes, the primary epidermal cells.
Purpose of the Study:
- * To identify the specific domain of M protein responsible for keratinocyte recognition.
- * To investigate the role of complement regulatory proteins in bacterial adherence.
Main Methods:
- * Construction and analysis of mutant M proteins.
- * Investigation of factor H and membrane cofactor protein (MCP) binding to M protein.
- * Competitive inhibition assays using purified MCP.
Main Results:
- * The C repeat domain of M protein is crucial for keratinocyte recognition.
- * Factor H binding to the M protein C repeat region blocks bacterial adherence.
- * M protein directly binds to MCP (CD46) on keratinocytes, inhibiting S. pyogenes adherence.
Conclusions:
- * The M protein's C repeat domain is essential for Streptococcus pyogenes adherence to keratinocytes.
- * Interaction with MCP is a significant factor in streptococcal skin colonization.
- * Targeting the M protein-MCP interaction could offer therapeutic strategies.