Sandbox 300: Difference between revisions
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==Function associated to this protein== | ==Function associated to this protein== | ||
Protein A has been identified as a cell surface protein of ''Staphylococcus aureus'' which contributes to the staphylococcal virulence. The virulence is mediated by the ability to interact with plasma protein<ref>Uhlén, M., Guss, B., Nilsson, B., Götz, F., & Lindberg, M. (1984). Expression of the gene encoding protein A in Staphylococcus aureus and coagulase-negative staphylococci. Journal of bacteriology, 159(2), 713-9</ref>. Protein A is able to bind to the Fc (constant region of IgG which is involved in effector functions) and the Fab fragment (also a part of Ig which is responsible for antigen recognition). The interactions of protein A with plasma proteins are mediated by five homologous domains, which are called E, D, A, B and C. Each of the homologous | Protein A has been identified as a cell surface protein of ''Staphylococcus aureus'' which contributes to the staphylococcal virulence. The virulence is mediated by the ability to interact with plasma protein<ref>Uhlén, M., Guss, B., Nilsson, B., Götz, F., & Lindberg, M. (1984). Expression of the gene encoding protein A in Staphylococcus aureus and coagulase-negative staphylococci. Journal of bacteriology, 159(2), 713-9</ref>. Protein A is able to bind to the Fc (constant region of IgG which is involved in effector functions) and the Fab fragment (also a part of Ig which is responsible for antigen recognition). The interactions of protein A with plasma proteins are mediated by five homologous domains, which are called E, D, A, B and C. Each of the homologous repeated domains comprises 56-61 residues, which are followed by a polymorphic variable repeated region, which is called Xr, and a conserved region Xc, which includes a cell wall attachment sequence<ref>O'Seaghdha, M., van Schooten, C. J., Kerrigan, S. W., Emsley, J., Silverman, G. J., Cox, D., Lenting, P. J. and Foster, T. J. (2006), Staphylococcus aureus protein A binding to von Willebrand factor A1 domain is mediated by conserved IgG binding regions. FEBS Journal, 273: 4831–4841</ref>. Each domain is able to bind one IgG molecule through its Fcγ binding site . The binding of protein A to the Fc fragment plays a major role in the virulence of ''Staphylococcus aureus'' as it competes with phagocytic cells for available IgG-Fc sites. This results in a reduction of IgG- mediated opsonization. | ||
The domains D and E of protein A are able to bind to the Fab fragments of immunoglobulins through variable (V) regions. The Fv-binding sites enable protein A to cross-link membrane IgM on B cells and therefore mediate the activation of these cells, which confers a superantigen function to protein A. Several features of the interactions of protein A with host B lymphocytes are similar to those of superantigens for T lymphocytes, which can cause various inflammatory diseases, such as toxic shock syndrome and food poisoning. | The domains D and E of protein A are able to bind to the Fab fragments of immunoglobulins through variable (V) regions. The Fv-binding sites enable protein A to cross-link membrane IgM on B cells and therefore mediate the activation of these cells, which confers a superantigen function to protein A. Several features of the interactions of protein A with host B lymphocytes are similar to those of superantigens for T lymphocytes, which can cause various inflammatory diseases, such as toxic shock syndrome and food poisoning. | ||
Furthermore it was shown that the staphylococcal protein A is able to activate the classical complement pathway. This activation depends on the binding of a VH3+ IgM molecule to protein A, which results in the generation of an inflammatory reaction. The protein A induced complement activation is another factor, which contributes to the staphylococcal virulence. | Furthermore it was shown that the staphylococcal protein A is able to activate the classical complement pathway. This activation depends on the binding of a VH3+ IgM molecule to protein A, which results in the generation of an inflammatory reaction. The protein A induced complement activation is another factor, which contributes to the staphylococcal virulence. | ||
Moreover, invasive ''Staphylococcus aureus disease'' are often associated with the complication of endovascular infections. In order to cause this kind of complication staphylococci must first adhere to endovascular foci and colonize these tissues. One of the factors released by endothelial cells and by platelets is the von Willbrrand factor (vWF). This factor mediates the adhesion of platelets at damaged endothelial sites. It was shown that vWF binds to and also promotes the adhesion of staphylococcal cells to vWF-absorbed surfaces. It could also be demonstrated that the recognition of vWF is mediated by the staphylococcal protein A. | Moreover, invasive ''Staphylococcus aureus disease'' are often associated with the complication of endovascular infections. In order to cause this kind of complication staphylococci must first adhere to endovascular foci and colonize these tissues. One of the factors released by endothelial cells and by platelets is the von Willbrrand factor (vWF). This factor mediates the adhesion of platelets at damaged endothelial sites. It was shown that vWF binds to and also promotes the adhesion of staphylococcal cells to vWF-absorbed surfaces. It could also be demonstrated that the recognition of vWF is mediated by the staphylococcal protein A. | ||
Protein A defective mutants have shown reduced virulence in murine models. These observations can be explained most likely by the antiphagocytic effect of protein A binding IgG Fc fragments<ref>Hartleib, J., Köhler, N., Dickinson, R. B., Chhatwal, G. S., Sixma, J. J., M, O., Foster, T. J., et al. (2000). Protein A is the von Willebrand factor binding protein on Staphylococcus aureus, 2149-2156</ref>. | Protein A defective mutants have shown reduced virulence in murine models. These observations can be explained most likely by the antiphagocytic effect of protein A binding IgG Fc fragments<ref>Hartleib, J., Köhler, N., Dickinson, R. B., Chhatwal, G. S., Sixma, J. J., M, O., Foster, T. J., et al. (2000). Protein A is the von Willebrand factor binding protein on Staphylococcus aureus, 2149-2156</ref>. | ||
==Medical implication== | ==Medical implication== | ||
Staphylococcus aureus is known to be a dangerous pathogen, responsible of food poisoning and localized or generalized infections. This bacterium is often associated to multi-resistant germ to antibiotics, and it causes problems in medical field. | |||
The pathogenicity of S. aureus is due to the protein A, which is an important virulence factor. | |||
The protein A permit the inhibition of the phagocytosis, the process of vesicular internalization of solid particles, because of the interaction with mammal antibodies. | |||
In a normal case of phagocytosis, the bacterium is eliminated during intracellular digestion, thanks to hydrolytic enzymes of phagocyte. At first, the particle is recognized and sticks on the phagocyte. The recognition is possible thanks to phagocyte membrane receptors, which recognize the Fc domain of immunoglobulins. Then the bacteria enter into the phagocyte by a process of endocytosis. The intracellular digestion takes place, and the bacterium is degraded by enzymes. To finish, cell fragments are removed by exocytosis. | |||
In the case of S.aureus, in the serum, the interaction between Fc domain and protein A leads to the attachment in a wrong direction of the IgG to the bacterium: then, the recognition is not allowed and the cascade of reactions necessary for phagocytosis does not occur. By stopping this process, bacterial colonization is allowed, through the growth and dissemination of bacteria into the organism. | |||
==Protein A in laboratories== | ==Protein A in laboratories== | ||
