Structural bases that underline Trypanosoma cruzi calreticulin proinfective, antiangiogenic and antitumor properties.
Microbes have developed mechanisms to resist the host immune defenses and some elicit antitumor immune responses. About 6 million people are infected with Trypanosoma cruzi, the protozoan agent of Chagas' disease, the sixth neglected tropical disease worldwide. Eighty years ago, G. Roskin and N. Klyuyeva proposed that T. cruzi infection mediates an anti-cancer activity. This observation has been reproduced by several other laboratories, but no molecular basis has been proposed. We have shown that the highly pleiotropic chaperone calreticulin (TcCalr, formerly known as TcCRT), translocates from the parasite ER to the exterior, where it mediates infection. Similar to its human counterpart HuCALR (formerly known as HuCRT), TcCalr inhibits C1 in its capacity to initiate the classical pathway of complement activation. We have also proposed that TcCalr inhibits angiogenesis and it is a likely mediator of antitumor effects. We have generated several in silico structural TcCalr models to delimit a peptide (VC-TcCalr) at the TcCalr N-domain. Chemically synthesized VC-TcCalr did bind to C1q and was anti-angiogenic in Gallus gallus chorioallantoic membrane assays. These properties were associated with structural features, as determined in silico. VC-TcCalr, a strong dipole, interacts with charged proteins such as collagen-like tails and scavenger receptors. Comparatively, HuCALR has less polarity and spatial stability, probably due to at least substitutions of Gln for Gly, Arg for Lys, Arg for Asp and Ser for Arg that hinder protein-protein interactions. These differences can explain, at least in part, how TcCalr inhibits the complement activation pathway and has higher efficiency as an antiangiogenic and antitumor agent than HuCALR.
['Peña Álvarez|Jaime|J|', 'Teneb|Jaime|J|', 'Maldonado|Ismael|I|', 'Weinberger|Katherine|K|', 'Rosas|Carlos|C|', 'Lemus|David|D|', 'Valck|Carolina|C|', 'Olivera-Nappa|Álvaro|Á|', 'Asenjo|Juan A|JA|', 'Ferreira|Arturo|A|']
D043924:Angiogenesis Modulating Agents D000818:Animals D000970:Antineoplastic Agents D037282:Calreticulin D002478:Cells, Cultured D014355:Chagas Disease D002642:Chick Embryo D003167:Complement Activation D015922:Complement C1q D006790:Host-Parasite Interactions D006801:Humans D056004:Molecular Dynamics Simulation D015394:Molecular Structure D054730:Protein Interaction Domains and Motifs D015800:Protozoan Proteins D016415:Sequence Alignment D014349:Trypanosoma cruzi
Trypanosoma cruzi calreticulin Complement C1q Molecular dynamics Protein modeling Tumor growth