Abstract:

The conserved regulon of Heat Shock Factor 1 in budding yeast contains chaperones

for general protein folding as well as Zinc Finger Protein Zpr1, whose essential role in

archaea and eukaryotes remains unknown. Here, we show that Zpr1 depletion causes

acute proteotoxicity driven by biosynthesis of misfolded eukaryotic translation

elongation factor 1A (eEF1A). Prolonged Zpr1 depletion leads to loss of eEF1A thereby

inducing the integrated stress response and inhibiting protein synthesis. Strikingly, we

show using two distinct biochemical reconstitution approaches that Zpr1 enables

eEF1A to achieve a conformational state resistant to protease digestion. Lastly, we use

a ColabFold model of the Zpr1-eEF1A complex to reveal a folding mechanism

mediated by Zpr1’s zinc finger and alpha helical hairpin structures. Our work uncovers

the long sought-after function of Zpr1 as a bespoke chaperone for one of the most

abundant proteins in the cell.