# eIF2A in translational control

> **NIH NIH R01** · CLEVELAND STATE UNIVERSITY · 2021 · $292,046

## Abstract

Initiation of protein synthesis in eukaryotes is a complex process requiring more than 12 different initiation
factors, comprising over 30 polypeptide chains. The functions of many of these factors have been established
in great detail; however, the precise role of some of them and their mechanism of action still remain not well
understood. eIF2A is a single chain 65 kDa protein that was initially believed to serve as the functional
homologue of prokaryotic IF2, since eIF2A and IF2 catalyze biochemically similar reactions, i.e. they stimulate
initiator methionyl-tRNA (Met-tRNAMeti) binding to the small ribosomal subunit. However, subsequent
identification of a heterotrimeric 126 kDa factor, eIF2() showed that this factor and not eIF2A is primarily
responsible for the binding of Met-tRNAMeti to 40S ribosomal subunits in eukaryotes. In mammals, four stress-
activated kinases reduce the level of active eIF2 by phosphorylating the eIF2subunit and, consequently,
reducing the global level of translation. However, translation of many cellular and viral proteins appeared to be
resistant to eIF2α phosphorylation despite requiring Met-tRNAMeti. It was found that a subset of factors,
including eIF2A, can promote efficient recruitment of Met-tRNAMeti to 40S/mRNA complexes under conditions
of inhibition of eIF2 activity, or its absence. Recently, eIF2A was also reported to be involved in non-AUG
dependent initiation in higher eukaryotes and the control of antigen presentation by major histocompatibility
complex (MHC) class I molecules, the integrated stress response and tumor initiation and progression. All of
these events were affected by eIF2A silencing in cellular models. Yet, the precise role of eIF2A in vivo, as well
as the precise mechanism of its action still remain largely enigmatic. There is a fundamental gap in our
understanding of how eIF2A functions in mammalian systems in vivo and ex vivo. To fill in this gap above and
to continue the physical and functional characterization of a eukaryotic/mammalian eIF2A, we have created a
viable homozygous eIF2A-total knockout mouse strain and obtained recombinant eIF2A expressed in E. coli
cells. The ultimate goal of this proposal is to understand the function of eIF2A in vivo and in vitro. This goal will
be achieved by a combination of in vitro, ex vivo and in vivo (mouse model) approaches. The outcome of this
proposal will be important for understanding the basic mechanisms of the translational control of gene
expression in higher eukaryotes, especially as part of the stress response.

## Key facts

- **NIH application ID:** 10085656
- **Project number:** 5R01GM128981-02
- **Recipient organization:** CLEVELAND STATE UNIVERSITY
- **Principal Investigator:** Anton A. Komar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $292,046
- **Award type:** 5
- **Project period:** 2020-01-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10085656

## Citation

> US National Institutes of Health, RePORTER application 10085656, eIF2A in translational control (5R01GM128981-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10085656. Licensed CC0.

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