Fuzzy recognition by the prokaryotic transcription factor HigA2 from Vibrio cholerae

San Hadži, Zala Živič, Matic Kovačič, Uroš Zavrtanik, Sarah Haesaerts, Daniel Charlier, Janez Plavec, Alexander N. Volkov, Jurij Lah () and Remy Loris ()
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San Hadži: Vrije Universiteit Brussel
Zala Živič: University of Ljubljana
Matic Kovačič: National Institute of Chemistry
Uroš Zavrtanik: University of Ljubljana
Sarah Haesaerts: Vrije Universiteit Brussel
Daniel Charlier: Vrije Universiteit Brussel
Janez Plavec: National Institute of Chemistry
Alexander N. Volkov: Vrije Universiteit Brussel
Jurij Lah: University of Ljubljana
Remy Loris: Vrije Universiteit Brussel

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract 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 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 intrinsically disordered region 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 intrinsically disordered region mediate electrostatic and hydrophobic interactions while “hovering” over the DNA operator. Sensitivity of the intrinsically disordered region to scrambling the sequence, position-specific contacts and absence of redundant, multivalent interactions, point towards a 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.

Date: 2024
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DOI: 10.1038/s41467-024-47296-3

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