Structural and functional characterization of 
eIF4E1 and eIF4E2 complexes involved in translational control

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Dokumentart: Dissertation
Date: 2018
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biochemie
Advisor: Izaurralde, Elisa (Prof. Dr.)
Day of Oral Examination: 2017-12-12
DDC Classifikation: 570 - Life sciences; biology
Keywords: Strukturbiologie , Proteinbiosynthese
Other Keywords: mRNA Translation
translational control
License: Publishing license including print on demand
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Protein synthesis is one of the costliest processes in the cell. Therefore, the initiation of translation is a tightly regulated process. One major control mechanism targets the activity or formation of the so-called eIF4F (eukaryotic initiation factor 4F) complex bound to the 5’ cap structure of an mRNA. This heterotrimeric complex, consisting of the RNA helicase eIF4A, the cap-binding protein eIF4E and the scaffold subunit eIF4G, is ultimately required for the recruitment of the 43S PIC (pre-initiation complex) to the mRNA, leading to subsequent scanning and initiation. The formation of the eIF4F complex is under the control of a group of inhibitory proteins known as eIF4E-binding proteins (4E-BPs), which bind to eIF4E and prevent its interaction with eIF4G. 4E-BPs comprise a group of functionally distinct proteins and include global translational repressors such as the three human proteins 4E-BP1-3, or large, multidomain proteins that likely act on an mRNA-specific level. Alternatively, the assembly of the eIF4F complex can be prevented by the eIF4E-homologous protein (4EHP or eIF4E2), which competes with eIF4E in binding to the 5’cap structure of an mRNA. Compared to the global repression by 4E-BPs, the later mechanism only acts on a message specific level. Comprehensive molecular insight into eIF4E- and 4EHP-complexes involved in the regulation of translation initiation was lacking. My doctoral work provides a fundamental structural and mechanistic understanding of the formation of these regulatory complexes. In my initial studies, I characterized the binding of various 4E-BPs to eIF4E and provided the first structural insights into an extended eIF4E-binding mode of different 4E-BPs. The structures revealed a conserved mode of interaction with eIF4E, despite the lack of sequence conservation. Additionally, in a collaborative project, I observed that the eIF4E-binding mode characteristic of 4E-BP complexes is also present in eIF4E-eIF4G complexes, expanding the knowledge on the mechanism of translation initiation and its regulation. Another part of my doctoral studies focused on 4E-BPs very specific functions and architecture. Specifically, I investigated the binding mode of an invertebrate-specific 4E-BP called Mextli. My studies unveiled an unexpected variation and evolutionary plasticity in the eIF4E-binding mode of Mextli homologs across species, which confer distinct functional properties to the respective eIF4E-complexes. I also studied 4EHP, the second member of the eIF4E protein family, and its specific interaction partners, the Grb10-interacting GYF domain-containing (GIGYF) proteins 1 and 2, and obtained the first crystal structures of theses 4EHP-specific binding partners bound to 4EHP. The molecular details of the 4EHP-GIGYF translational repressor complex explain why GIGYF proteins bind to 4EHP and not to eIF4E. Overall, my doctoral studies revealed new insights on eIF4E-related complexes and their diverse roles in posttranscriptional gene regulation.

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