Eukaryotic Translation Factors and Protein Synthesis Dynamics

Eukaryotic protein synthesis is coordinated by a suite of translation factors that regulate initiation, elongation and termination. Initiation involves assembly of a pre-initiation complex, recruitment of mRNA via the cap-binding machinery and scanning for the start codon. During elongation, canonical elongation factors deliver aminoacyl-tRNAs and promote translocation, while eIF5A uniquely facilitates peptide-bond formation at challenging sequences, notably polyproline motifs. Activation of eIF5A requires post-translational hypusination, a two-step modification catalysed by deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). Beyond its role in elongation, hypusinated eIF5A influences translation termination and mRNA stability. Parallel efforts have revealed that ABCF ATPases bind the ribosome to resolve stalling at charged or proline-rich stretches, cooperating with elongation factors to sustain translational throughput. Recent structural analyses, including cryo-EM of the eIF5A–DHPS complex, have illuminated the molecular basis of hypusine synthesis and the mechanism by which specific tRNA elements direct factor binding, advancing our understanding of dynamic control in eukaryotic protein synthesis.

Research from Nature Portfolio

Recent structural studies have elucidated the mechanism of eIF5A hypusination at atomic resolution. A high-resolution cryo-EM reconstruction of the human eIF5A–DHPS complex revealed key interactions that stabilise the transition state of deoxyhypusine formation, clarifying how pathogenic mutations diminish modification efficiency. In a complementary approach, in vitro reprogramming of tRNAPro identified specific D-loop and D-stem structural motifs that are recognised by elongation factor P (EF-P), the bacterial functional orthologue of eIF5A. This work defined how these elements guide factor recruitment and accelerate peptide-bond formation at Pro–Pro junctions, providing a foundational link between tRNA architecture and elongation factor activity.

Eukaryotic Translation Factors and Protein Synthesis Dynamics publication trend

The graph below shows the total number of articles in eukaryotic translation factors and protein synthesis dynamics across all publications each year (not limited to Nature Index journals).

Technical terms

eIF5A: A unique eukaryotic translation factor that, once hypusinated, promotes peptide-bond formation at sequences prone to ribosomal pausing, including polyproline tracts.

Hypusination: A two-step post-translational modification of eIF5A involving deoxyhypusine synthase and deoxyhypusine hydroxylase, essential for factor activation and function.

Ribosomal stalling: A translational pause resulting from amino acid motifs that impede peptide-bond formation or translocation, requiring specialised factors for efficient resolution.

ABCF ATPase: A subfamily of ATP-binding cassette proteins that bind the ribosome to alleviate pausing at difficult sequences independently of membrane transport functions.

References

1. Cryo-EM structure of human eIF5A-DHS complex reveals the molecular basis of hypusination-associated neurodegenerative disorders. Nature Communications (2023).
2. Resolution of ribosomal stalling by EF-P and ABCF ATPases YfmR and YkpA/YbiT. Nucleic Acids Research (2024).
3. DHPS‐Mediated Hypusination Regulates METTL3 Self‐m6A‐Methylation Modification to Promote Melanoma Proliferation and the Development of Novel Inhibitors. Advanced Science (2024).
4. Essential structural elements in tRNAPro for EF-P-mediated alleviation of translation stalling. Nature Communications (2016).