Unraveling an ancient eEF1A biogenesis pathway that safeguards cellular protein synthesis

Protein biosynthesis is secured by ubiquitous chaperones that are associated with translating ribosomes.

This project unravels a new concept in the co-translational protein folding paradigm by uncovering a biogenesis pathway that is specific for one of the most highly expressed eukaryotic proteins, the essential translation elongation factor eEF1A.

In ongoing studies, we have found that during synthesis of eEF1A, the novel chaperone Chp1 is recruited to the ribosome together with chaperone NAC, where they secure the ample production of eEF1A as well as protects the cellular proteostasis network from extensive collateral damage caused by eEF1A misfolding.

In this 4-year project, using a combination of state-of-the-art techniques in molecular cell biology, including selective ribosome profiling, we will (1) identify and characterize the function of the full set of biogenesis factors in the eEF1A biogenesis pathway, (2) elucidate how damage caused by aberrant eEF1A biogenesis impacts on the protein biosynthesis capacity of cells and (3) determine how the biogenesis pathway controls the synthesis of neurodegenerative eEF1A mutants.

Uncovering the molecular cell biology of this nascent eEF1A-specific pathway is of importance for both biological as well as medical sciences.

The project provides a foundation to understand how cells secure the co-translational folding of ancient and critical proteins that are hard to fold, as well as the complex interactions at the ribosomal tunnel.