Fuzzy recognition by the prokaryotic transcription factor HigA2 from Vibrio cholerae

San Hadzi, Zala Zivic, Matic Kovacic, Uroš Zavrtanik, Sarah Haesaerts, Daniel Charlier, Janez Plavec, Oleksandr Volkov, Jurij Lah, Remy Loris

Onderzoeksoutput: Articlepeer review


Disordered protein sequences can exhibit different binding modes, ranging from well-ordered folding-upon-binding to highly dynamic fuzzy binding. The primary function of the intrinsically disordered region (IDR) of the antitoxin HigA2 from Vibrio cholerae is to neutralize HigB2 toxin through ultra-high-affinity folding-upon-binding interaction. Here, we show that the same IDR can also mediate fuzzy interactions with its operator DNA and, through interplay with the folded helix-turn-helix domain, regulates transcription from the higBA2 operon. NMR, SAXS, ITC and in vivo experiments converge towards a consistent picture where a specific set of residues in the IDR mediate electrostatic and hydrophobic interactions while hovering over the DNA operator. Sensitivity of the IDR to scrambling the sequence, position-specific contacts and absence of redundant, multivalent interactions, point towards a novel, more specific type of fuzzy binding. Our work demonstrates how a bacterial regulator achieves dual functionality by utilizing two distinct interaction modes within the same disordered sequence.
Originele taal-2English
Aantal pagina's12
TijdschriftNat Commun
Nummer van het tijdschrift1
StatusPublished - 10 apr 2024

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Publisher Copyright:
© The Author(s) 2024.


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