Assen Marintchev, Ph.D.
Associate Professor of Pharmacology, Physiology & Biophysics
Research
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, a major target of regulation in response to a number of stress factors, in a process known as the integrated stress response (ISR). Dysregulated ISR is a causative factor in Alzheimer’s Disease and other neurodegenerative disorders. 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. An area of particular interest is the coordination between translation initiation and ISR.