Abstract
Upon triggering by their inducer, signal transduction ATPases with numerous domains (STANDs), initially in monomeric resting forms, multimerize into large hubs that activate target macromolecules. This process requires conversion of the STAND conserved core (the NOD) from a closed form encasing an ADP molecule to an ATP-bound open form prone to multimerize. In the absence of inducer, autoinhibitory interactions maintain the NOD closed. In particular, in resting STAND proteins with an LRR- or WD40-type sensor domain, the latter establishes interactions with the NOD that are disrupted in the multimerization-competent forms. Here, we solved the first crystal structure of a STAND with a tetratricopeptide repeat sensor domain, PH0952 from Pyrococcus horikoshii, revealing analogous NOD-sensor contacts. We use this structural information to experimentally demonstrate that similar interactions also exist in a PH0952 homolog, the MalT STAND archetype, and actually contribute to the MalT autoinhibition in vitro and in vivo. We propose that STAND activation occurs by stepwise release of autoinhibitory contacts coupled to the unmasking of inducer-binding determinants. The MalT example suggests that STAND weak autoinhibitory interactions could assist the binding of inhibitory proteins by placing in register inhibitor recognition elements born by two domains.
Highlights
Signal transduction ATPases with numerous domains (STAND) are a family of AAA+ related ATPases involved in a wide range of cellular activities [1,2]
These results suggest that NBD–sensor autoinhibitory contacts are a general feature of STAND proteins, which was unexpected considering the variety of sensor domain types exhibited by that superfamily
To identify interactions between the STAND conserved core (the nucleotide-binding oligomerization domain (NOD)) and the sensor domains of MalT possibly involved in the autoinhibition process, we first tried to solve the X-ray structure of MalT and close homologs from proteobacteria
Summary
Signal transduction ATPases with numerous domains (STAND) are a family of AAA+ related ATPases involved in a wide range of cellular activities [1,2]. Upon activation by the cognate inducer molecule, these proteins build up multimeric hubs that trigger a signaling cascade. In the absence of inducer, STAND proteins are generally maintained in a monomeric autoinhibited resting form by numerous intramolecular interactions as well as interactions with inhibitory molecules. The hallmark of STAND ATPases is a conserved core called nucleotide-binding oligomerization domain (NOD), which is responsible for nucleotide binding and protein oligomerization. The NOD comprises the NBD-HD (nucleotide-binding domain-helical domain) module of AAA+ proteins [3] fused to a STAND-specific WHD (winged-helix domain) at the C-terminus. STAND ATPases generally contain at least one effector domain that is located at either protein
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