Deciphering the structural basis of translation initiation regulation

• Applicant: Professor Dr. Janosch Hennig
• Subject Area: Structural Biology ; Biochemistry ; Biophysics
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 508497078

Translation is a core mechanism of life, ensuring a constant supply of proteins to each cell of the host organism. The workings of the major molecular machine behind this cellular procedure, the ribosome, are well understood to atomistic detail and in a range of organisms. In contrast, it is far from understood how this process is regulated in a spatial and temporal manner by general and abundant RNA binding proteins. Almost unchartered is the field on how RNA structures are involved in translation regulation. The 5’-3’ proximity in mRNAs during translation initiation is universally accepted, but how RNA structures are involved in forming a “closed-loop” and how a large translation repression complex affects this communication between termini is not understood. This proposal aims to obtain an at least near-atomic resolution structure of a complete Drosophila translation repression complex at different stages of assembly during translation initiation. All involved components are highly conserved in humans, where they fulfil the same or similar roles of which some are implicated in cancer development and progression. The structure determination of this complex and a range of sub-complexes will be achieved by cryo-EM in combination with data from NMR, X-ray crystallography and small-angle scattering. Moreover, the assembly and dynamics of both regulation processes will be monitored by single molecule fluorescence microscopy and all data will be validated in a cellular system. The outcome will provide unprecedented insights of how RNA structures and general RNA binding proteins regulate translation initiation.

• DFG Programme: Research Grants