The Role of Cytoplasmic mRNA Cap-Binding Protein Complexes in Trypanosoma brucei and Other Trypanosomatids

Abstract

Trypanosomatid protozoa are unusual eukaryotes that are well known for having unusual ways of controlling their gene expression. The lack of a refined mode of transcriptional control in these organisms is compensated by several post-transcriptional control mechanisms, such as control of mRNA turnover and selection of mRNA for translation, that may modulate protein synthesis in response to several environmental conditions found in different hosts. In other eukaryotes, selection of mRNA for translation is mediated by the complex eIF4F, a heterotrimeric protein complex composed by the subunits eIF4E, eIF4G, and eIF4A, where the eIF4E binds to the 5'-cap structure of mature mRNAs. In this review, we present and discuss the characteristics of six trypanosomatid eIF4E homologs and their associated proteins that form multiple eIF4F complexes. The existence of multiple eIF4F complexes in trypanosomatids evokes exquisite mechanisms for differential mRNA recognition for translation.

Keywords: Kinetoplastids; eIF4E; translation initiation.

Figure 1

Schematic representation of EIF4E1 and EIF4E2 homologs from T. brucei and L. major. The eIF4E core regions are represented in grey; black boxes represent insertions within these core regions; tryptophan residues involved in cap binding are highlighted in blue; residues involved in eIF4G-binding are highlighted in red. The E-value numbers and the domain boundaries were generated through sequence searches using the on line tool Pfam Database [80,81].

Figure 2

Summary of the complexes formed EIF4E1 and EIF4E2. Available data indicates that EIF4E1 might be involved in translation repression when bound to 4E-IP, and translation stimulation when bound to EIF3 complex through EIF3a subunit interaction. EIF4E2 interaction with its specific partner and their biological function still needs to be addressed.

Figure 3

Schematic representation of EIF4E3 and EIF4E4 homologs from T. brucei and L. major. The eIF4E core regions are represented in grey; insertions within these core regions are represented by black boxes; tryptophan residues involved in cap binding are highlighted in blue; and residues involved in eIF4G-binding are highlighted in red. The Boxes 1, 2 and 3 represent three conserved regions likely involved in binding to PABP homologs and localized within the N-terminal extensions of EIF4E3 and EIF4E4. The E-value numbers and the domain boundaries were generated through sequence searches using the on line tool Pfam Database [80,81].

Figure 4

Summary of eIF4F complexes formed by EIF4E4 or EIF4E3 and their respective partners. EIF4E4 forms the main eIF4F complex in trypanosomatids involved in translation by interacting with EIF4G3 (which also binds to EIF4A1), and to PABP1 through three small regions (Boxes B1, B2 and B3) at its N-terminal extension which bind to the PABPC domain of PABP1. Similar composition might perhaps be found on the secondary eIF4F complex formed by EIF4E3 with EIF4G4, EIF4A1 and a PABP homologue.

Figure 5

Schematic model of EIF4E5 and EIF4E6 homologues from T. brucei and L. major. eIF4E core region is represented in grey rectangle; Insertions inside the core region of EIF4E5 and EIF4E6 are represented in black boxes; Tryptophan residues involved in cap binding are highlighted in blue; Residues involved (or equivalent) in eIF4G-binding are highlighted in red. The E-value numbers and the domain boundaries were generated through sequence searches using the on line tool Pfam Database [80,81].

Figure 6

Schematic representation of the eIF4F-like complexes formed by EIF4E5. One eIF4F-like complex performed by EIF4E5 is composed by its interaction with EIF4G1, that binds to the guanylyltransferase/methyltransferase domain-containing protein G1-IP (which seems to be regulated by a 14-3-3 protein homolog) and G1-IP2, an RNA binding protein. The second EIF4E5 complex is composed by its interaction with EIF4G2, which also binds to a protein of unknown function called here G2-IP.

Figure 7

Schematic representation of the eIF4F-like complex of EIF4E6.

Figure 8

Summary of the eIF4F(-like) complexes formed by the six EIF4E of trypanosomatids. A dynamic picture of multiple eIF4E homologs acting as part of different eIF4F complexes that might regulate the mRNA fate on different aspects of translation initiation.