Eukaryotic elongation factor 2 (eEF2) requires extensive chaperone support due to its complex multi-domain structure and high abundance. However, the full complement of chaperones involved in its folding remains elusive. Here, we identify a protein that bears TetraTriCopeptide repeats, Emw1/TTC27, as a critical chaperone for eEF2 folding. This essential protein has been conserved throughout the eukaryotic lineage. Using the budding yeast Saccharomyces cerevisiae, we show that Emw1/TTC27 physically interacts with eEF2, and levels of the elongation factor decline when activity of Emw1/TTC27 is limited. Emw1/TTC27 facilitates folding during eEF2 synthesis rather than stabilizing pre-folded eEF2. This role parallels that of Hgh1, another known eEF2 chaperone, with evidence suggesting that Emw1/TTC27 and Hgh1 cooperate, as dual impairment of these proteins severely restricts yeast growth. In the hgh1Δ background expressing a hypomorphic allele of EMW1, additional deletion of one of the two eEF2 paralogs is lethal, underscoring the essential role of Emw1/TTC27 in preventing toxic folding intermediates during eEF2 biogenesis. Taken together, our data suggest that Emw1/TTC27 is a critical addition to the eEF2 chaperone network, acting co-translationally with other chaperones to ensure eEF2 folding and maintain proteostasis.

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Journal Article

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Yang M, Li R, Mikolajczak AI, Wright VA, Hassan M, Vaughan CK, Prescott TAK, Heritz JA, Mollapour M, Panaretou B

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