# Mechanism of translation initiation through the non-canonical initiation factor eIF2A

> **NIH NIH F31** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $40,207

## Abstract

ABSTRACT
Many diseases, including cancer and those resulting from viral infections, are associated with alterations in the
function of host translational machinery. These alterations are referred to as “ribosomal hijacking” and occur
through various mechanisms. I propose to explore a poorly characterized mechanism utilized by pathogenic
mRNAs. This mechanism involves the inhibition of canonical host proteins involved in translation and results in
the activation of a non-canonical translation pathway mediated by the alternate translation initiation factor
eIF2A, a distinct protein from the canonical eIF2 complex. Under stress conditions, phosphorylation of the
alpha-subunit of eIF2 results in general downregulation of cellular protein synthesis. Yet, mRNAs that contain
internal ribosome entry sites (IRES), such as hepatitis C virus (HCV) and proto-oncogene tyrosine-protein
kinase Src (c-Src), circumvent eIF2-mediated translation initiation through an eIF2A-mediated alternate
mechanism. The role of eIF2A in translation of these mRNAs underscores its significance as this mechanism
exhibits a significant connection to human health and disease. Exploring the biochemical and structural basis
for eIF2A binding and recruitment of tRNA to form an initiation complex with the ribosome will increase our
understanding of eIF2A function and the role it plays in the translation of pathogenic mRNA. To elucidate the
mechanism of eIF2A-mediated initiation I will determine high resolution structures of eIF2A loading tRNA onto
the ribosome in an initiation state via cryoEM. Furthermore, I will employ crystallography techniques to
determine high resolution structures of eIF2A-tRNA complexes to determine the basis for tRNA binding and
selectivity by eIF2A.

## Key facts

- **NIH application ID:** 10902766
- **Project number:** 1F31GM154483-01
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Aaron Ferrell
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $40,207
- **Award type:** 1
- **Project period:** 2024-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10902766

## Citation

> US National Institutes of Health, RePORTER application 10902766, Mechanism of translation initiation through the non-canonical initiation factor eIF2A (1F31GM154483-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10902766. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*