Hidden states within disordered regions of the CcdA antitoxin protein

Virginia M. Burger, Alexandra Vandervelde, Jelle Hendrix, Albert Konijnenberg, Frank Sobott, Remy Loris, Colin M. Stultz

Onderzoeksoutput: Articlepeer review

7 Citaten (Scopus)

Samenvatting

The bacterial toxin-antitoxin system CcdB-CcdA provides a mechanism for the control of cell death and quiescence. The antitoxin protein CcdA is a homodimer composed of two monomers that each contain a folded N-terminal region and an intrinsically disordered C-terminal arm. Binding of the intrinsically disordered C-terminal arm of CcdA to the toxin CcdB prevents CcdB from inhibiting DNA gyrase and thereby averts cell death. Accurate models of the unfolded state of the partially disordered CcdA antitoxin can therefore provide insight into general mechanisms whereby protein disorder regulates events that are crucial to cell survival. Previous structural studies were able to model only two of three distinct structural states, a closed state and an open state, that are adopted by the C-terminal arm of CcdA. Using a combination of free energy simulations, single-pair Förster resonance energy transfer experiments, and existing NMR data, we developed structural models for all three states of the protein. Contrary to prior studies, we find that CcdA samples a previously unknown state where only one of the disordered C-terminal arms makes extensive contacts with the folded N-terminal domain. Moreover, our data suggest that previously unobserved conformational states play a role in regulating antitoxin concentrations and the activity of CcdA's cognate toxin. These data demonstrate that intrinsic disorder in CcdA provides a mechanism for regulating cell fate.

Originele taal-2English
Pagina's (van-tot)2693-2701
Aantal pagina's9
TijdschriftJ. Am. Chem. Soc.
Volume139
Nummer van het tijdschrift7
DOI's
StatusPublished - 22 feb 2017

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