In Silico Characterization of Calcineurin from Pathogenic Obligate Intracellular Trypanosomatids: Potential New Biological Roles.

Patricio R Orrego,Jorge E Araya,Mauro Cortez,Mayela Serrano-Rodríguez

doi:10.3390/biom11091322

Abstract

Calcineurin (CaN) is present in all eukaryotic cells, including intracellular trypanosomatid parasites such as Trypanosoma cruzi (Tc) and Leishmania spp. (Lspp). In this study, we performed an in silico analysis of the CaN subunits, comparing them with the human (Hs) and looking their structure, post-translational mechanisms, subcellular distribution, interactors, and secretion potential. The differences in the structure of the domains suggest the existence of regulatory mechanisms and differential activity between these protozoa. Regulatory subunits are partially conserved, showing differences in their Ca2+-binding domains and myristoylation potential compared with human CaN. The subcellular distribution reveals that the catalytic subunits TcCaNA1, TcCaNA2, LsppCaNA1, LsppCaNA1_var, and LsppCaNA2 associate preferentially with the plasma membrane compared with the cytoplasmic location of HsCaNAα. For regulatory subunits, HsCaNB-1 and LsppCaNB associate preferentially with the nucleus and cytoplasm, and TcCaNB with chloroplast and cytoplasm. Calpain cleavage sites on CaNA suggest differential processing. CaNA and CaNB of these trypanosomatids have the potential to be secreted and could play a role in remote communication. Therefore, this background can be used to develop new drugs for protozoan pathogens that cause neglected disease.

Highlights

IntroductionPeople all over the world are affected by leishmaniasis and American trypanosomiasis, two neglected tropical diseases that infect over 6 and 12 million people, respectively [1,2,3]
It was possible to establish that the domain structure is diverse among the catalytic subunits of CaN of intracellular trypanosomatids, establishing potential different post-translational regulation mechanisms observed in the analysis of cleavage by calpains, or by the phosphorylation patterns in the regulatory domains of the catalytic subunits, in the A1 subunits in Leishmania (LsppCaNA1 and LsppCaNA1_var)
In the case of regulatory subunits, the domain structure is different, with LsppCaNB being more similar to the human regulatory subunit (HsCaNB-1) than to TcCaNB, the binding affinity for Ca2+ is conserved between TcCaNB and LsppCaNB

Summary

Introduction

People all over the world are affected by leishmaniasis and American trypanosomiasis, two neglected tropical diseases that infect over 6 and 12 million people, respectively [1,2,3]. Several issues, including a lack of safe/optional drugs, parasite resistance, and ineffective insect vector control, have caused researchers to race to develop more effective treatments for diseases [4], increasing the current alternative studies with promising results [5,6,7]. These vector-borne diseases are caused by protozoan parasites of the Trypanosomatidae family, Leishmania spp.

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Conclusion