ATP-Binding and Hydrolysis in Inflammasome Activation

Abstract

The prototypical model for NOD-like receptor (NLR) inflammasome assembly includesnucleotide-dependent activation of the NLR downstream of pathogen- or danger-associatedmolecular pattern (PAMP or DAMP) recognition, followed by nucleation of hetero-oligomericplatforms that lie upstream of inflammatory responses associated with innate immunity. Asmembers of the STAND ATPases, the NLRs are generally thought to share a similar model of ATPdependentactivation and effect. However, recent observations have challenged this paradigm toreveal novel and complex biochemical processes to discern NLRs from other STAND proteins. Inthis review, we highlight past findings that identify the regulatory importance of conserved ATPbindingand hydrolysis motifs within the nucleotide-binding NACHT domain of NLRs and explorerecent breakthroughs that generate connections between NLR protein structure and function.Indeed, newly deposited NLR structures for NLRC4 and NLRP3 have provided unique perspectiveson the ATP-dependency of inflammasome activation. Novel molecular dynamic simulations ofNLRP3 examined the active site of ADP- and ATP-bound models. The findings support distinctionsin nucleotide-binding domain topology with occupancy of ATP or ADP that are in turndisseminated on to the global protein structure. Ultimately, studies continue to reveal how the ATPbindingand hydrolysis properties of NACHT domains in different NLRs integrate with signalingmodules and binding partners to control innate immune responses at the molecular level.

Identification of ultra-rare genetic variants in Pediatric Acute Onset Neuropsychiatric Syndrome (PANS) by exome and whole genome sequencing

“…A total of four patients with ultra-rare variants in NLRC4 were found in our two cohorts (including patient 17 who also has a SHANK3 variant). Two variants, c.772T>C (p.C258R) and c.928C>T (p.R310X) map to the NACHT domain, which has intrinsic ATPase activity and facilitates self-oligomerization 59 . Gain of function mutations in this region lead to severe hyperinflammatory disorders 55 .…”

Techniques to Study Inflammasome Activation and Inhibition by Small Molecules

“…The NLR inflammasome sensors present ATP hydrolytic activity required for inflammasome assembly [ 89 ]. Measurement of the ATPase activity of the NLRs in the presence or absence of inhibitors not only gives information about the direct inhibitory effect, but is also an approach to know the mechanism of action of the inhibitor.…”

Sodium houttuyfonate attenuates neurological defects after traumatic brain injury in mice via inhibiting NLRP3 inflammasomes

“…The NOD-like receptor with pyrin domain containing-3 (NLRP3) inflammasome, which is expressed in microglia and endotheliocyte, is one of the most clinically important elements of inflammatory activity. [6] The NLRP3 inflammasome is an intracellular protein complex that contains NLRP3, an apoptosis-associated speck-like protein containing a CARD domain (ASC) and cysteine protease pro-caspase-1. [7] In the CNS, NLRP3 inflammasome is considered necessary for initiating and activating the inflammatory response via recognizing dangerassociated molecular patterns (DAMPs).…”