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Characterization of Multi-subunit Protein Complexes of Human MxA Using Non-denaturing Polyacrylamide Gel-electrophoresis
Published on: October 28, 2016
The nonideal coiled coil of M protein and its multifarious functions in pathogenesis
1Department of Chemistry and Biochemistry, University of California, San Diego, CA, 92093-0375, USA. pghosh@ucsd.edu
Abstract:
The M protein is a major virulence factor of Streptococcus pyogenes (group A Streptococcus, GAS). This gram-positive bacterial pathogen is responsible for mild infections, such as pharyngitis, and severe invasive disease, like streptococcal toxic shock syndrome. M protein contributes to GAS virulence in multifarious ways, including blocking deposition of antibodies and complement, helping formation of microcolonies, neutralizing antimicrobial peptides, and triggering a proinflammatory and procoagulatory state. These functions are specified by interactions between M protein and many host components, especially C4BP and fibrinogen. The former interaction is conserved among many antigenically variant M protein types but occurs in a strikingly sequence-independent manner, and the latter is associated in the M1 protein type with severe invasive disease. Remarkably for a protein of such diverse interactions, the M protein has a relatively simple but nonideal α-helical coiled coil sequence. This sequence nonideality is a crucial feature of M protein. Nonideal residues give rise to specific irregularities in its coiled-coil structure, which are essential for interactions with fibrinogen and establishment of a proinflammatory state. In addition, these structural irregularities are reminiscent of those in myosin and tropomyosin, which are targets for crossreactive antibodies in patients suffering from autoimmune sequelae of GAS infection.
Insights
Streptococcus pyogenes M protein, a key virulence factor, uses structural irregularities to interact with host components, causing disease and potentially autoimmune issues. Understanding these interactions is crucial for combating GAS infections.
Area of Science:
- Microbiology
- Molecular Biology
- Immunology
Background:
- Streptococcus pyogenes (group A Streptococcus, GAS) is a pathogen causing mild to severe infections.
- M protein is a major GAS virulence factor, mediating diverse interactions with host components.
- M protein's functions include immune evasion, microcolony formation, and inducing inflammation.
Purpose of the Study:
- To investigate the structural basis of M protein's interactions with host factors like C4BP and fibrinogen.
- To understand how M protein's sequence nonideality contributes to GAS virulence and disease severity.
- To explore potential links between M protein structure and autoimmune sequelae.
Main Methods:
- Analysis of M protein's α-helical coiled coil sequence and structure.
- Investigating interactions with host proteins, particularly C4BP and fibrinogen.
- Comparing M protein structural features to other proteins like myosin and tropomyosin.
Main Results:
- M protein possesses a nonideal α-helical coiled coil structure crucial for its functions.
- Sequence nonideality leads to structural irregularities essential for fibrinogen interaction and inflammation.
- M protein's structural features resemble those targeted in autoimmune diseases post-GAS infection.
Conclusions:
- M protein's nonideal structure is central to its role as a virulence factor in Streptococcus pyogenes.
- Specific structural irregularities facilitate critical host interactions, contributing to disease pathogenesis.
- M protein's structure may play a role in the development of autoimmune conditions following GAS infections.
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