Rheumatic fever and rheumatic heart damage are recognized to be sequelae of group A streptococcal infection. Antibodies cross-reactive with streptococcal components and mammalian muscle have been demonstrated in the sera of acute rheumatic fever patients. Our previous studies have shown that M protein, the type-specific antiphagocytic determinant of the group A streptococcus, has a coiled-coil structure similar to the mammalian muscle tropomyosin. More recently, we have established the complete amino acid sequence of a biologically active fragment of the M protein from the type 5 streptococcus, a 'rheumatogenic' serotype. This sequence is the first of its kind among the M proteins. A detailed analysis has now revealed that (i) the heptad periodicity in the nonpolar and charged amino acid residues, a characteristic of alpha-helical coiled-coil proteins, extends essentially throughout its entire length, and (ii) the distribution of charged functional groups in the external positions of its coiled-coil structure is different in the N- and the C-terminal regions of the molecule. In the proposed study, the potential significance of the similarity of the streptococcal M protein to mammalian coiled-coil proteins, and its relevance to the presence in the sera of acute rheumatic fever patients, of antibodies cross-reactive with streptococcal antigens and mammalian muscle will be investigated. Towards this objective, mammalian coiled-coil proteins tropomyosin and myosin will be isolated from human cardiac tissue, and their antigenic similarities with streptococcal M proteins will be examined by immunochemical methods. Also, sera from rheumatic fever patients will be examined for the presence of antibodies cross-reactive with M protein and muscle proteins. The contribution of charged functional groups for the stability of the coiled-coil structure, and for the integrity of the opsonogenic epitope of the M molecule will be explored by chemical modification studies. The structural relatedness of the M5 protein, as well as M proteins from other 'rheumatogenic' serotypes, to those of the 'nephritogenic' serotypes will be examined by comparative peptide map and immunochemical analysis. The results of these studies are expected to help us better understand (i) some aspects of the molecular basis for the pathogenesis of rheumatic fever, and thus possibly shed new light on the pathogenesis of autoimmune diseases in general and (ii) provide an insight into the structural characteristics governing the common antiphagocytic property of the M protein molecules.
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