ATP-Binding and Hydrolysis in Inflammasome Activation
Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB T2N 4Z6, Canada
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Author to whom correspondence should be addressed.
Academic Editor: Massimo Bertinaria
Molecules 2020, 25(19), 4572; https://doi.org/10.3390/molecules25194572
Received: 15 September 2020 / Revised: 2 October 2020 / Accepted: 3 October 2020 / Published: 7 October 2020
(This article belongs to the Special Issue Inflammasome Inhibitors)
The prototypical model for NOD-like receptor (NLR) inflammasome assembly includes nucleotide-dependent activation of the NLR downstream of pathogen- or danger-associated molecular pattern (PAMP or DAMP) recognition, followed by nucleation of hetero-oligomeric platforms that lie upstream of inflammatory responses associated with innate immunity. As members of the STAND ATPases, the NLRs are generally thought to share a similar model of ATP-dependent activation and effect. However, recent observations have challenged this paradigm to reveal novel and complex biochemical processes to discern NLRs from other STAND proteins. In this review, we highlight past findings that identify the regulatory importance of conserved ATP-binding and hydrolysis motifs within the nucleotide-binding NACHT domain of NLRs and explore recent breakthroughs that generate connections between NLR protein structure and function. Indeed, newly deposited NLR structures for NLRC4 and NLRP3 have provided unique perspectives on the ATP-dependency of inflammasome activation. Novel molecular dynamic simulations of NLRP3 examined the active site of ADP- and ATP-bound models. The findings support distinctions in nucleotide-binding domain topology with occupancy of ATP or ADP that are in turn disseminated on to the global protein structure. Ultimately, studies continue to reveal how the ATP-binding and hydrolysis properties of NACHT domains in different NLRs integrate with signaling modules and binding partners to control innate immune responses at the molecular level.
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Keywords:
inflammasome; NACHT domain; NOD-like receptor; NLR; NLRP; ATPase; molecular dynamic simulation; nucleotide
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- Supplementary File 1:
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Externally hosted supplementary file 1
Doi: 10.5281/zenodo.4029653
Link: https://zenodo.org/record/4029653
Description: Methods S1: Methods for MD Simulation -
Externally hosted supplementary file 2
Doi: 10.5281/zenodo.4029653
Link: https://zenodo.org/record/4029653
Description: Video S1: ADP-NLRP3 10 ns Molecular Dynamic Simulation -
Externally hosted supplementary file 3
Doi: 10.5281/zenodo.4029653
Link: https://zenodo.org/record/4029653
Description: Video S2: ATP-NLRP3 10 ns Molecular Dynamic Simulation
MDPI and ACS Style
Sandall, C.F.; Ziehr, B.K.; MacDonald, J.A. ATP-Binding and Hydrolysis in Inflammasome Activation. Molecules 2020, 25, 4572. https://doi.org/10.3390/molecules25194572
AMA Style
Sandall CF, Ziehr BK, MacDonald JA. ATP-Binding and Hydrolysis in Inflammasome Activation. Molecules. 2020; 25(19):4572. https://doi.org/10.3390/molecules25194572
Chicago/Turabian StyleSandall, Christina F.; Ziehr, Bjoern K.; MacDonald, Justin A. 2020. "ATP-Binding and Hydrolysis in Inflammasome Activation" Molecules 25, no. 19: 4572. https://doi.org/10.3390/molecules25194572
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