The synthesis of proteins using genetic information is a fundamental process in all life forms. In higher organisms, the process is tightly controlled, much more so than in prokaryotes, and much of this regulation occurs during the initial steps of translation. Although translation initiation is a fundamental and indispensable process, many aspects of initiation mechanisms are poorly understood. Furthermore, a number of non-canonical pathways exist for the translation initiation in eukaryotes and it is likely that this number may increase with yet undiscovered pathways.
Understanding translation initiation and its regulation is critically important because dysregulation of initiation is associated with several human metabolic disorders and cancers. Initiation is also the target of many viruses, which hijack host initiation and employ internal ribosome entry site (IRES)-dependent translation initiation allowing translation to proceed without the need for a full set of initiation factors. Regulation of translation initiation also plays an important role in many key life processes like early embryonic development, learning and memory and the response to cellular stress.
Structural understanding of translation initiation pathways has just begun, largely owing to the recent advancement in cryo-electron microscopy (cryo-EM) that permits us to undertake structural studies of such large molecular machines at high resolution without the bottleneck of crystallization. We aim to understand the molecular mechanisms involved in the regulation of translation initiation using biochemical, mutational and structural approaches. While cryo-EM will be used to determine 3D structures of large macromolecular complexes, the structures of individual proteins and smaller macromolecular complexes (not amenable to cryo-EM) will be determined using X-ray crystallography.
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