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 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 (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 and human rhodopsin loop into our anti-P2 monoclonal antibody homology model allowed to explore their interactions.The solution structure of peptides P0 and P2 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

Searching for New Clues about the Molecular Cause of Endomyocardial Fibrosis by Way of In Silico Proteomics and Analytical Chemistry

“…Note that this composition is associated with extensive negativity of the peptides- overall charge, uniquely imposed by the amino acids Asparagine and glutamine that are most present within the constitution of both peptides. This is not surprising, since both these terminal peptides are found localized within the acidic C-termini of the T. cruzi ribosomal proteins [16], [17]. Specifically, these findings tally with the findings of Martin et al.…”

“…Note that the binding site of the peptides is a positive charged cavity. This work is reminiscent of the recent findings towards a better understanding of the molecular pathology of Chaga's disease, citation [17] Martin OA, Villegas ME, Aguilar CF (2009) Three-dimensional studies of pathogenic peptides from the c-terminal of Trypanosoma cruzi ribosomal P proteins and their interaction with a monoclonal antibody structural model. PMC Biophys .…”

“…Martin et al. [17] have recently described, using 3-dimensional modeling and docking experiments, a more clear interaction of the structural elements involved in the autoimmune mechanism of anti-P auto-antibodies cross-reaction and stimulation of the β1-adrenoreceptor, results that may lead eventually to the development of treatments to abolish receptor mediated symptoms in Chaga's disease ( see Figure 1 for illustration [ 17 ] ) . Given the prior observed related pathology in both diseases, we hypothesized, that molecular mimicry may explain the pathology seen in both diseases too.…”

Identification of Differentially Expressed Proteins from Leishmania amazonensis Associated with the Loss of Virulence of the Parasites

“…a ) Spots match ID number obtained from ImageMaster Platinum;b ) Name of the identified protein;c ) Uniprot identification code;d ) Experimentally predicted and expected isoelectric point ( pI );e ) Experimentally predicted and expected molecular weight ( Mr , in kDa);f ) Number of identified peptides by MS;g ) Percentage of the protein sequence covered by identified peptides;h ) Normalized data from R0 represented by mean values of each condition divided by R30 value;i ) Fold represents the maximum spot intensity mean value of the conditions divided by the smallest value;j ) One-way ANOVA ( P <0.01) obtained from spot analysis;k ) Biological functions according to NCBI, UniProt, and Gene Ontology databases;l ) Biological activity and/or immunological application described in other studies: [22] Tull et al, 2010; [23] Oliveira et al, 2006; [24] Daifalla et al, 2011; [25] Iyer et al, 2008; [26] Hunger-Glaser et al, 1999; [27] Werbovetz et al, 1999; [28] Feng et al, 2011; [29] Niemirowicz et al, 2007; [30] Hunger-Glaser et al, 1997; [31] Alcolea et al, 2009; [32] Bhaskar et al, 2012; [33] Khanra et al, 2012; [34] Berberich et al, 2003; [35] Moore et al, 1996; [36] Swenerton et al, 2011; [37] Hummadi et al, 2006; [38] Martins et al, 2006; [39] Burns et al, 1993; [40] Kushawaha et al, 2011; [41] Misra et al, 2005; [42] Bringaud et al, 1995; [43] Eggleson et al, 1999; [44] Mureev et al, 2007; [45] Steiner et al, 2007; [46] Martínez-Rodríguez et al, 2012; [47] Drummelsmith et al, 2004; [48] Achour et al, 2002; [49] Buda et al, 2013; [50] Alcolea et al, 2011; [51] Martín et al, 2009; [52] Silva et al, 2012. The proteins were identified through the data included in ...…”

Computational prediction and analysis of the DR6–NAPP interaction

“…Over the near term, progress can be made toward the development of a high‐quality DR6–GFD NAPP structural model through the application of computational methods, specifically, homology modeling and protein–protein docking methods. Indeed, numerous studies have been published that describe the successful use of multimethod computational work‐flows to model protein–protein interactions 2–10. Where possible, such studies use protein crystal structures.…”