A ribosome-associating chaperone mediates GTP-driven vectorial folding of nascent eEF1A

Ibrahim M. Sabbarini, Dvir Reif, Kibum Park, Alexander J. McQuown, Anjali R. Nelliat, Charlotte Trejtnar, Volker Dötsch, Eugene I. Shakhnovich, Andrew W. Murray and Vladimir Denic ()
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Ibrahim M. Sabbarini: Harvard University
Dvir Reif: Harvard University
Kibum Park: Harvard University
Alexander J. McQuown: Harvard University
Anjali R. Nelliat: Harvard Medical School
Charlotte Trejtnar: Goethe University
Volker Dötsch: Goethe University
Eugene I. Shakhnovich: Harvard University
Andrew W. Murray: Harvard University
Vladimir Denic: Harvard University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Eukaryotic translation elongation factor 1A (eEF1A) is a highly abundant, multi-domain GTPase. Post-translational steps essential for eEF1A biogenesis are carried out by bespoke chaperones but co-translational mechanisms tailored to eEF1A folding remain unexplored. Here, we use AlphaPulldown to identify Ypl225w (also known as Chp1, Chaperone 1 for eEF1A) as a conserved yeast protein predicted to stabilize the N-terminal, GTP-binding (G) domain of eEF1A against its misfolding propensity, as predicted by computational simulations and validated by microscopy analysis of ypl225wΔ cells. Proteomics and biochemical reconstitution reveal that Ypl225w functions as a co-translational chaperone by forming dual interactions with the eEF1A G domain nascent chain and the UBA domain of ribosome-bound nascent polypeptide-associated complex (NAC). Lastly, we show that Ypl225w primes eEF1A nascent chains for binding to GTP as part of a folding mechanism tightly coupled to chaperone recycling. Our work shows that an ATP-independent chaperone can drive vectorial folding of nascent chains by co-opting G protein nucleotide binding.

Date: 2025
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DOI: 10.1038/s41467-025-56489-3

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