Flanking Disorder of the Folded αα-Hub Domain from Radical Induced Cell Death1 Affects Transcription Factor Binding by Ensemble Redistribution: Flanking disorder tunes the RCD1-RST ensemble

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Protein intrinsic disorder is essential for organization of transcription regulatory interactomes. In these interactomes, the majority of transcription factors as well as their interaction partners have co-existing order and disorder. Yet, little attention has been paid to their interplay. Here, we investigate how order is affected by flanking disorder in the folded αα-hub domain RST from Radical-Induced Cell Death1 (RCD1), central in a large interactome of transcription factors. We show that the intrinsically disordered C-terminal tail of RCD1-RST shifts its conformational ensemble towards a pseudo-bound state through weak interactions with the ligand-binding pocket. An unfolded excited state is also accessible on the ms timescale independent of surrounding disordered regions, but its population is lowered by 50% in their presence. Flanking disorder additionally lowers transcription factor binding-affinity without affecting the dissociation rate constant, in accordance with similar bound-states assessed by NMR. The extensive dynamics of the RCD1-RST domain, modulated by flanking disorder, is suggestive of its adaptation to many different transcription factor ligands. The study illustrates how disordered flanking regions can tune fold and function through ensemble redistribution and is of relevance to modular proteins in general, many of which play key roles in regulation of genes.

OriginalsprogEngelsk
Artikelnummer167320
TidsskriftJournal of Molecular Biology
Vol/bind433
Udgave nummer24
Antal sider15
ISSN0022-2836
DOI
StatusUdgivet - 2021

Bibliografisk note

Funding Information:
We thank Signe A. Sj?rup, Joachim Berg Mortensen, Ida Holm R?nshof, Katherine R. Kemplen and Charlotte O'Shea for technical assistance, Katrine Bugge for valuable discussions and Andreas Prestel for NMR support. This work was supported by the Danish Research Councils [#4181-00344 and #9040-00164B to B.B.K. and K.S.], the Novo Nordisk Foundation Challenge Program ? REPIN [#NNF18OC0033926 to B.B.K. and K.S.] and the Lundbeck foundation to M.B.A.K. The NMR infrastructure was supported by Novo Nordisk Foundation infrastructure grant [#NNF18OC0032996, cOpenNMR] and Villum Fonden. Funding for open access charge: Novo Nordisk Foundation/#NNF18OC0033926. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Funding Information:
We thank Signe A. Sjørup, Joachim Berg Mortensen, Ida Holm Rønshof, Katherine R. Kemplen and Charlotte O’Shea for technical assistance, Katrine Bugge for valuable discussions and Andreas Prestel for NMR support. This work was supported by the Danish Research Councils [#4181-00344 and #9040-00164B to B.B.K. and K.S.], the Novo Nordisk Foundation Challenge Program – REPIN [#NNF18OC0033926 to B.B.K. and K.S.] and the Lundbeck foundation to M.B.A.K. The NMR infrastructure was supported by Novo Nordisk Foundation infrastructure grant [#NNF18OC0032996, cOpenNMR] and Villum Fonden. Funding for open access charge: Novo Nordisk Foundation/#NNF18OC0033926.

Publisher Copyright:
© 2021 Elsevier Ltd

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