Journal
ELIFE
Volume 11, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.76630
Keywords
fold-switching; NusG proteins; RfaH; metamorphic proteins; KOW domains; E; coli
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Funding
- European Cooperation in Science and Technology [CA15126]
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This study investigates the thermodynamic stability and structural dynamics of two-domain protein RfaH and NusG/Spt5-KOW domains. The findings suggest that the folding transition in RfaH is driven by transiently structured elements in the unfolded conformation.
The two-domain protein RfaH, a paralog of the universally conserved NusG/Spt5 transcription factors, is regulated by autoinhibition coupled to the reversible conformational switch of its 60-residue C-terminal Kyrpides, Ouzounis, Woese (KOW) domain between an alpha-hairpin and a beta-barrel. In contrast, NusG/Spt5-KOW domains only occur in the beta-barrel state. To understand the principles underlying the drastic fold switch in RfaH, we elucidated the thermodynamic stability and the structural dynamics of two RfaH- and four NusG/Spt5-KOW domains by combining biophysical and structural biology methods. We find that the RfaH-KOW beta-barrel is thermodynamically less stable than that of most NusG/Spt5-KOWs and we show that it is in equilibrium with a globally unfolded species, which, strikingly, contains two helical regions that prime the transition toward the alpha-hairpin. Our results suggest that transiently structured elements in the unfolded conformation might drive the global folding transition in metamorphic proteins in general.
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