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

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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)

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.

Suggested Citation

  • Ibrahim M. Sabbarini & Dvir Reif & Kibum Park & Alexander J. McQuown & Anjali R. Nelliat & Charlotte Trejtnar & Volker Dötsch & Eugene I. Shakhnovich & Andrew W. Murray & Vladimir Denic, 2025. "A ribosome-associating chaperone mediates GTP-driven vectorial folding of nascent eEF1A," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56489-3
    DOI: 10.1038/s41467-025-56489-3
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    References listed on IDEAS

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    3. Edward L. Huttlin & Raphael J. Bruckner & Joao A. Paulo & Joe R. Cannon & Lily Ting & Kurt Baltier & Greg Colby & Fana Gebreab & Melanie P. Gygi & Hannah Parzen & John Szpyt & Stanley Tam & Gabriela Z, 2017. "Architecture of the human interactome defines protein communities and disease networks," Nature, Nature, vol. 545(7655), pages 505-509, May.
    4. Melania Minoia & Jany Quintana-Cordero & Katharina Jetzinger & Ilgin Eser Kotan & Kathryn Jane Turnbull & Michela Ciccarelli & Anna E. Masser & Dorina Liebers & Eloïse Gouarin & Marius Czech & Vasili , 2024. "Chp1 is a dedicated chaperone at the ribosome that safeguards eEF1A biogenesis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
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