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

Olivier Danot (1)

1 Génétique Moléculaire

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.

Mots clés: ATPase; STAND; signal transduction; ligand binding; chemical cross-linking; disulfide bond; maltotriose; transcription activation

Domaines: Sciences du Vivant [q-bio]; Biochimie [q-bio.BM]

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, 2015, 43 (6), pp.3089-3099. ⟨10.1093/nar/gkv158⟩. ⟨pasteur-01160453⟩