Synthesis runs counter to directional folding of a nascent protein domain

Xiuqi Chen, Nandakumar Rajasekaran, Kaixian Liu and Christian M. Kaiser ()
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Xiuqi Chen: Johns Hopkins University
Nandakumar Rajasekaran: Johns Hopkins University
Kaixian Liu: Johns Hopkins University
Christian M. Kaiser: Johns Hopkins University

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: Abstract Folding of individual domains in large proteins during translation helps to avoid otherwise prevalent inter-domain misfolding. How folding intermediates observed in vitro for the majority of proteins relate to co-translational folding remains unclear. Combining in vivo and single-molecule experiments, we followed the co-translational folding of the G-domain, encompassing the first 293 amino acids of elongation factor G. Surprisingly, the domain remains unfolded until it is fully synthesized, without collapsing into molten globule-like states or forming stable intermediates. Upon fully emerging from the ribosome, the G-domain transitions to its stable native structure via folding intermediates. Our results suggest a strictly sequential folding pathway initiating from the C-terminus. Folding and synthesis thus proceed in opposite directions. The folding mechanism is likely imposed by the final structure and might have evolved to ensure efficient, timely folding of a highly abundant and essential protein.

Date: 2020
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DOI: 10.1038/s41467-020-18921-8

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