Bioinformatic Analysis of Two TOR (Target of Rapamycin)-Like Proteins Encoded by Entamoeba histolytica Revealed Structural Similarities with Functional Homologs

Patricia L A Muñoz-Muñoz,Rosa E Mares-Alejandre,Samuel G Meléndez-López,Marco A Ramos-Ibarra

doi:10.3390/genes12081139

Patricia L A Muñoz-Muñoz, Rosa E Mares-Alejandre + Show 2 more

Open Access

https://doi.org/10.3390/genes12081139

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Journal: Genes	Publication Date: Jul 28, 2021
Citations: 2	License type: CC BY 4.0

Affiliation: Autonomous University of Baja California

Abstract

The target of rapamycin (TOR), also known as FKBP-rapamycin associated protein (FRAP), is a protein kinase belonging to the PIKK (phosphatidylinositol 3-kinase (PI3K)-related kinases) family. TOR kinases are involved in several signaling pathways that control cell growth and proliferation. Entamoeba histolytica, the protozoan parasite that causes human amoebiasis, contains two genes encoding TOR-like proteins: EhFRAP and EhTOR2. To assess their potential as drug targets to control the cell proliferation of E. histolytica, we studied the structural features of EhFRAP and EhTOR2 using a biocomputational approach. The overall results confirmed that both TOR amoebic homologs share structural similarities with functional TOR kinases, and show inherent abilities to form TORC complexes and participate in protein-protein interaction networks. To our knowledge, this study represents the first in silico characterization of the structure-function relationships of EhFRAP and EhTOR2.

Highlights

The target of rapamycin, TOR, is a conserved Ser/Thr protein kinase that belongs to the eukaryotic PIKK family (phosphatidylinositol 3-kinase (PI3K)-related kinases) [1]
The yeast proteins TOR1p and TOR2p were first identified in Saccharomyces cerevisiae as point mutations that conferred a resistance to rapamycin [2,3], an antifungal antibiotic produced by Streptomyces hygroscopicus [4,5]
The keyword search within the AmoebaDB repository returned two genes encoding TOR-like proteins (E. histolytica HM-1:IMSS genome database), annotated as putative FKBPrapamycin associated protein (FRAP), on referred to as EhFRAP (291.7 kDa, encoded by EHI_155160), and putative phosphatidylinositol 3-kinase Tor 2, on referred to as EhTOR2 (269.5 kDa, encoded by EHI_169320)

Summary

Introduction

The target of rapamycin, TOR ( known as FKBP-rapamycin associated protein, FRAP), is a conserved Ser/Thr protein kinase that belongs to the eukaryotic PIKK family (phosphatidylinositol 3-kinase (PI3K)-related kinases) [1]. Affinity studies showed that the FKBP-rapamycin complex binds more tightly to the FRB domain than rapamycin alone (about 2000-fold), suggesting that the rapamycin-TOR interactions in the absence of FKBP would have minimal effects under physiological conditions. These studies indicated that protein-protein interactions are important for the FKBP-rapamycin-TOR complex stability [8]. This ternary complex inhibits TOR functions by blocking its structural capability to form TORC1 or TORC2, the multiprotein complexes involved in several cell functions [9,10]

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