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How 'arm-twisting' by the inducer triggers activation of the MalT transcription factor, a typical signal transduction ATPase with numerous domains (STAND)

Abstract : Signal transduction ATPases with numerous domains (STAND) get activated through inducer-dependent assembly into multimeric platforms. This switch relies on the conversion of their nucleotide-binding oligomerization domain (NOD) from a closed, ADP-bound form to an open, ATP-bound form. The NOD closed form is stabilized by contacts with the arm, a domain that connects the NOD to the inducer-binding domain called the sensor. How the inducer triggers NOD opening remains unclear. Here, I pinpointed the NOD-arm interface of the MalT STAND transcription factor, and I generated a MalT variant in which this interface can be covalently locked on demand , thereby trapping the NOD in the closed state. By characterizing this locked variant, I found that the inducer is recognized in two steps: it first binds to the sole sensor with low affinity, which then triggers the recruitment of the arm to form a high-affinity arm-sensor inducer-binding site. Strikingly, this high-affinity binding step was incompatible with arm-NOD contacts maintaining the NOD closed. Through this toggling between two mutually exclusive states reminiscent of a single-pole double-throw switch, the arm couples inducer binding to NOD opening, shown here to precede nucleotide exchange. This scenario likely holds for other STANDs like mammalian NLR innate immunity receptors.
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Contributor : Olivier Danot <>
Submitted on : Friday, June 5, 2015 - 2:34:34 PM
Last modification on : Monday, January 13, 2020 - 5:08:08 PM
Long-term archiving on: : Tuesday, September 15, 2015 - 11:37:12 AM

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Olivier Danot. How 'arm-twisting' by the inducer triggers activation of the MalT transcription factor, a typical signal transduction ATPase with numerous domains (STAND). Nucleic Acids Research, Oxford University Press, 2015, 43 (6), pp.3089-3099. ⟨10.1093/nar/gkv158⟩. ⟨pasteur-01160453⟩

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