Publications by authors named "Amaranta Muniz Malvezzi"
Recognition of the mRNA 5' end is a critical step needed for translation initiation. This step is performed by the cap binding protein eIF4E, which joins the larger eIF4G subunit to form the eIF4F complex. Trypanosomatids have a minimum of five different eIF4F-like complexes formed through specific but not well-defined interactions between four different eIF4E and five eIF4G homologues.
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- The TcK2 protein kinase of Trypanosoma cruzi is similar to the human kinase PERK and is crucial for the parasite's proliferation in mammalian cells; its absence leads to increased differentiation into infective forms.
- A study confirmed that TcK2-null cells express proteins associated with infective stages and showed decreased phosphorylation of factors that promote growth, resulting in lower proliferation rates.
- Screening of 379 kinase inhibitors identified Dasatinib and PF-477736 as effective inhibitors of TcK2, with Dasatinib showing potential as a therapeutic target for Chagas disease due to its selective efficacy against normal amastigotes but not against TcK2-depleted parasites.
Article Synopsis
- Trypanosomatids primarily manage gene expression after transcription, focusing on mRNA processing and translation control, unlike most eukaryotes, which mainly regulate synthesis via phosphorylation of eIF2.
- In T. cruzi, the causative agent of Chagas' disease, we found that levels of eIF2α decrease in infective forms, indicating reduced protein synthesis and a rise in phosphorylation in proliferative stages before transforming into infective stages.
- Mutations or overexpression of eIF2α led to significant changes in the parasite's proteins, resulting in less production of infective trypomastigotes, alongside alterations in surface protein composition that may affect infection capabilities.
The integrated stress response in eukaryotic cells is an orchestrated pathway that leads to eukaryotic Initiation Factor 2 alpha subunit (eIF2α) phosphorylation at ser51 and ultimately activates pathways to mitigate cellular damages. Three putative kinases (k1, k2, and k3) are found in the genome, the flagellated parasite that causes Chagas disease. These kinases present similarities to other eukaryotic eIF2α kinases, exhibiting a typical insertion loop in the kinase domain of the protein.
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