{"id":{"repo_id":"tuebingen","oai_identifier":"oai:publikationen.uni-tuebingen.de:10900/79834"},"canonical_url":"https://search.dev.ndltd.org/etd/tuebingen/oai:publikationen.uni-tuebingen.de:10900/79834","repository":{"repo_id":"tuebingen","name":"Universität Tübingen","base_url":"https://publikationen.uni-tuebingen.de/oai/request"},"display":{"title":"Structural and functional characterization of eIF4E1 and eIF4E2 complexes involved in translational control","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Peter, Daniel"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2018,"date_issued":"2018","date_published":"2018","updated_at":"2026-08-21T22:21:56Z","subjects":[],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["hdl:10900/79834"],"render_values":[{"text":"hdl:10900/79834","href":null,"code":true}]}]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"source_record":{"url":"https://publikationen.uni-tuebingen.de/oai/request?verb=GetRecord&metadataPrefix=mets&identifier=oai%3Apublikationen.uni-tuebingen.de%3A10900%2F79834","prefix":"mets"},"metadata_groups":[{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2018"]},{"key":"dc:type","label":"Dc Type","values":["PhDThesis"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["hdl:10900/79834"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.other","label":"Dc Description Other","values":["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."]},{"key":"dc:title","label":"Title","values":["Structural and functional characterization of eIF4E1 and eIF4E2 complexes involved in translational control"]}]}],"canonical_facts":{"dc:date.issued":["2018"],"dc:description.other":["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."],"dc:identifier":["hdl:10900/79834"],"dc:title":["Structural and functional characterization of eIF4E1 and eIF4E2 complexes involved in translational control"],"dc:type":["PhDThesis"]},"updated_at":"2026-08-21T22:21:56Z"}