Three-dimensional studies of pathogenic peptides from the c-terminal of Trypanosoma cruziribosomal P proteins and their interaction with a monoclonal antibody structural model

Abstract

The acidic C-terminal peptides from Trypanosoma cruzi ribosomal P proteins are the major target of the antibody response in patients suffering Chagas chronic heart disease. It has been proposed that the disease is triggered by the cross-reaction of these antibodies with the second extra cellular loop of the (beta)1-adrenoreceptor, brought about by the molecular mimicry between the acidic C-terminal peptides and the receptor´s loop. To improve the understanding of the structural basis of the autoimmune response against heart receptors, the 3-dimensional structure of the C-terminal peptides of Trypanosoma cruzi ribosomal proteins P0 (EDDDDDFGMGALF) and P2(beta) (EEEDDDMGFGLFD) were solved using the Electrostaticaly Driven MonteCarlo method. Their structures were compared with the second extra-cellular loop of our homology model of human rhodopsin and the existing experimental NMR structures of the C-terminal peptides from human P0 (EESDDDMGFGLFD) and from Leishmania braziliensis P0 (EEADDDMGFGLFD). Docking of Trypanosoma cruzi peptides P0, P2(beta) and human rhodopsin loop into our anti-P2(beta) monoclonal antibody homology model allowed to explore their interactions. The solution structure of peptides P0 and P2(beta) can be briefly described as a bend. Although the global conformations of the peptides are not identical they shared a common region of four residues (3 to 6) that have a similar structure. The structural alignment of the five peptides also showed a surprising conformational similarity for the same residues. The antibody model and docking studies revealed a most remarkable feature in the active site, a positively charged, narrow and deep cavity where the acidic residues 3 to 6 were accommodated. These results suggest that the most important elements in the molecular peptide recognition by the antibody may be the shape of the loop and the presence of negative charges in positions 3?5 (P0, P2(beta)) or a negative charge in position 4 (rhodopsin loop). This work describes clearly the interactions of the structural elements involved in the autoimmune mechanism of anti-P auto-antibodies cross-reaction and stimulation of the (beta)1-adrenoreceptor and the visual pigment rhodopsin. Results from this study could lead eventually to the development of treatments to abolish receptor mediated symptoms in Chagas.