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Crystallographic studies on eukaryotic translation initiation factors and on components of the eubacterial protein degradation machinery
English title
Crystallographic studies on eukaryotic translation initiation factors and on components of the eubacterial protein degradation machinery
Applicant
Baumann Ulrich
Number
120174
Funding scheme
Project funding (Div. I-III)
Research institution
Universität Köln Institut für Biochemie
Institution of higher education
University of Berne - BE
Main discipline
Biophysics
Start/End
01.04.2008 - 30.06.2011
Approved amount
399'000.00
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Keywords (8)
metalloprotease; translation initiation; eIF4A; eIF4G; crystal structure; FtsH; AAA+ protease; X-ray
Lay Summary (English)
Lead
Lay summary
Protein synthesis and degradation are tightly controlled key events in all living cells. Translation initiation is one of the stages where the rate of synthesis can be influenced. In the cap-dependent initiation a set of about 12 eukaryotic translation initiation factors ensures the fidelity of the assembly of an elongation-competent 80S ribosome on the proper start codon. The ternary complex eIF4F, which consists of the cap-binding protein eIF4E, the DEAD-box RNA-helicase eIF4A and the scaffold protein eIF4G, is a central player and responsible for recruitment of the 43S pre-initiation complex to the 5’ end of the mRNA as well as for the subsequent scanning process. Protein-protein interactions are crucial for the fidelity and rate of translation initiation and their atomic details should be elucidated. The interaction between eIF4G and eIF4A is essential for RNA-helicase stimulation. The demand for helicase activity is very pronounced in the translation of messages with long and structured 5’-untranslated regions, as they occur in the majority of growth- and proliferation related mRNAs. Unregulated protein synthesis during tumorigenesis is therefore linked to upregulation of eIF4F. Hence disruption of the eIF4A-eIF4G interface should be a worthwhile approach for developing new drugs. Intracellular protein degradation is performed by large proteolytic assemblies (AAA+ proteases), which denature and digest their substrates under ATP consumption. Here, the chemical energy stored in ATP is transformed via conformational rearrangements into a mechanical force that is used for substrate unfolding and translocation. Closer understanding of their mode of action is currently hampered by the lack of information on their 3D structures. Specific aims of this research project are: (i) characterization of protein-protein interaction surfaces in eIFs; (ii) determination of the eiF4G-controled conformational changes and the helicase mechanism of eIF4A; (iii) development of small molecules that are able to disrupt eIF4A-eIF4G complex formation; (iv) elucidation of the conformational changes occurring during the ATPase cycle of AAA+ proteases, especially of the essential metalloprotease FtsH.We employ X-ray crystallography, site-directed mutagenesis and spectroscopic methods in order to derive structure-function relationships.Expected results are more detailed pictures of protein-protein interaction surfaces that are of general interest for virtually all processes in a cell. Crystal structures of RNA-helicases and AAA+ proteases in different nucleotide-dependent conformations will greatly advance our understanding on how these molecules function.
Direct link to Lay Summary
Last update: 21.02.2013
Responsible applicant and co-applicants
Name
Institute
Baumann Ulrich
Department für Chemie Universität zu Köln
Employees
Name
Institute
Baumgartner Renato
Departement für Chemie, Biochemie und Pharmazie Universität Bern
Oberholzer Anselm
Departement für Chemie, Biochemie und Pharmazie Universität Bern
Associated projects
Number
Title
Start
Funding scheme
108262
Kristallographische Studien an eukaryotischen Translationsinitiationsfaktoren und Komponenten der bakteriellen Proteinabbaumaschinerie
01.04.2005
Project funding (Div. I-III)
-