Assen G. Marintchev, PhD
|Institution||Boston University School of Medicine|
|Department||Physiology & Biophysics|
|Address||700 Albany St., (W336)|
Boston MA 02118
Molecular Mechanisms of Eukaryotic Translation Initiation and its Regulation:
Control of protein synthesis (translation) is vital for cell proliferation and differentiation. Initiation of translation is typically rate-limiting and is the main target of regulation. In cancer cells, multiple components of the translation initiation machinery are up-regulated in response to the demand for high rates of protein synthesis. The potential of using inhibitors of translation initiation for anti-cancer therapy was demonstrated in recent years and currently presents an active area of research.
Translation initiation is the process of locating the correct translation start codon on the mRNA and the assembly of an active ribosome, ready for translation. It requires a number of eukaryotic translation initiation factors (eIFs) and consists of several steps: initiation complex assembly; binding to mRNA; scanning; start codon recognition; and finally joining of the large ribosomal subunit to form a ribosome with a bound initiator Met-tRNAi ready to translate the mRNA. The initiator Met-tRNAi is delivered to the ribosome as a complex with eIF2-GTP. One eIF2-GTP:Met-tRNAi complex is “consumed” in every translation initiation cycle, with release of eIF2-GDP and deacylated initiator tRNAi. Regeneration of the eIF2-GTP:Met-tRNAi complex from eIF2-GDP and Met-tRNAi is catalyzed by the nucleotide exchange factor (GEF) eIF2B (reviewed in Marintchev and Wagner, 2004).
Our work is focused on studying the architecture of the translation initiation complexes, the molecular mechanisms of key steps in the process, and their regulation. The long-term goal is to build a detailed mechanistic and quantitative model of translation initiation as a whole, and learn how to rationally manipulate the system for the purposes of cancer therapy and treatment of metabolic disorders. Two areas of particular interest are the coordination between start codon selection and ribosomal subunit joining, and the regeneration of the eIF2-GTP:Met-tRNAi complex.
- Fluorescence anisotropy
- Protein structure
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