Structural bases that underline Trypanosoma cruzi calreticulin proinfective,antiangiogenic and antitumor properties |
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| Institution: | 1. University of Chile, Faculty of Physical and Mathematical Sciences, CeBiB, Chile;2. University of Chile, Faculty of Medicine, ICBM, Immunology Disciplinary Program, Chile;3. University of Chile, Faculty of Medicine, Anatomy and Developmental Biology Disciplinary Program, ICBM, Experimental and Molecular Embryology Laboratory, Chile;1. Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil;2. Núcleo Multidisciplinar de Pesquisa UFRJ – Xerém em Biologia (NUMPEX-BIO), Campus Duque de Caxias Professor Geraldo Cidade – Universidade Federal do Rio de Janeiro, Duque de Caxias, Rio de Janeiro, Brazil;3. Laboratório Interdisciplinar de Pesquisas Médicas, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Brazil;4. Núcleo de Doenças Infecciosas/ Núcleo de Biotecnologia- Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil;5. Laboratório de Imunopatologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Brazil;6. Faculdade de Medicina, Centro de Pesquisa em Tuberculose, Universidade Federal do Rio de Janeiro, Brazil;7. Instituto de Veterinária, Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ, Brazil;1. Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan, China;2. Academy of Medical Science, Zhengzhou University, Zhengzhou, 450001, Henan, China;3. Henan Key Laboratory of Tumor Epidemiology, Zhenghzou University, Zhengzhou, 450052, Henan, China;4. Department of Clinical Laboratory, Fuwai Central China Cardiovascular Hospital, Zhengzhou, 451464, Henan, China;5. Department of Clinical Laboratory, Zhengzhou Hospital of Traditional Chinese Medicine, Zhengzhou, 450000, Henan, China;1. Singapore Immunology Network (SIgN), A*STAR, Singapore;2. Department of Microbiology and Immunology, National University of Singapore (NUS), Singapore, Singapore;1. Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, USA;2. Department of Diagnosis and Surgery, UNESP-State University of Sao Paulo, School of Dentistry at Araraquara, Araraquara, SP, Brazil;3. Department of Physical Therapy, University of Florida Health Science Center, Gainesville, FL, USA;4. Department of Stomatology, School of Dentistry, Federal University of Goias (UFG), Goiania, GO, Brazil;5. Department of Foundational Sciences, College of Dental Medicine, East Carolina University, Greenville, NC, USA;1. Laboratorio de Oncología Experimental, Instituto de Medicina Experimental (IMEX)-CONICET, Academia Nacional de Medicina, Buenos Aires, Argentina;2. Laboratorio de Fisiología de los Procesos Inflamatorios, Instituto de Medicina Experimental (IMEX)-CONICET, Academia Nacional de Medicina, Buenos Aires, Argentina;3. Laboratorio de Inmunología Experimental, Instituto de Medicina Experimental (IMEX)-CONICET, Academia Nacional de Medicina, Buenos Aires, Argentina |
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| Abstract: | 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. |
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| Keywords: | Complement C1q Tumor growth Protein modeling Molecular dynamics |
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