As arquiteturas das proteínas quinases Akt/PKB e PDK1 que atuam na via Fosfatidilinositol 3-quinase (PI3K): uma evolução particular de domínios proteicos em tripanossomatídeos

Abstract

Akt/PKB (Protein Kinase B) participates in several cellular processes, including cellular proliferation, protein and lipid synthesis, glucose transport and cell migration, playing a central role in cell survival. Akt/PKB and PDK1 (Phosphoinositide-dependent kinase-1) are downstream effectors of PI3 kinase (Phosphoinositide 3-kinase) and belong to the cAMP-dependent protein kinase AGC family. Akt/PKB proteins share an architecture consisting of a C-terminal regulatory domain (PF00433), a central kinase domain (PF00069) and a N-terminal pleckstrin homology – PH (PF00169) domain for binding phosphoinositides. PDK1 is crucial for the activation of Akt/PKB which in turn regulates hundreds of downstream effectors by phosphorylation, including mTORC1 and the FOXO (Forkhead box protein O) family of transcription factors. In this study, we searched for Akt/PKB and PDK1 proteins among sequenced and annotated trypanosomatid genomes. We used the profiles that characterize each protein family in all translated CDS of 26 Leishmania and 18 Trypanosoma genomes obtained from TriTrypDB v5.5. We identified 28 Akt/PKBs and 201 PDK1 proteins, and only one copy of Akt/PKB coding sequence per genome, except for Trypanosoma cruzi Sylvio strain, which had two sequences. In the case of PDK1, several sequences were found per genome. Akt/PKB with a PH domain at the N-terminus has not been identified in fungi or plants but occurs both in basal eukaryotes such as Dictyostelium and in higher eukaryotes. This suggests that the ancestral Akt/PKB kinase possessed a PH domain that was lost in other species. We also find several proteins with a FYVE domain, possibly acting on lipid binding instead of PH domain. The proteins with distinct architectures did not group with the AGC kinase family. Therefore, it is necessary to review these proteins classification in trypanosomatids, given that the occurrence of new domain organizations that are group specific suggests that protein kinases achieved diversity functional roles to regulate a variety of biological processes.