Conformation switching of AIM2 PYD domain revealed by NMR relaxation and MD simulation

Wang, Haobo; Yang, Lijiang; Niu, Xiaogang

doi:10.1016/j.bbrc.2016.03.131

Cited by 8 publications

(4 citation statements)

References 27 publications

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“…Recently, Huber et al have described the intrinsic flexibility and behavior of NLRP14 PYD in different physiological condition . Wang and coauthors have studied the molecular switching of AIM2 PYD ‐helix‐α3 using a combined approach of NMR relaxation experiment and MD simulation …”

Section: Discussionmentioning

confidence: 78%

POP1 might be recruiting its type‐Ia interface for NLRP3‐mediated PYD‐PYD interaction: Insights from MD simulation

Maharana

Vats

Gautam

et al. 2017

J of Molecular Recognition

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Inflammasomes are multiprotein caspase-activating complexes that enhance the maturation and release of proinflammatory cytokines (IL-1β and IL-18) in response to the invading pathogen and/or host-derived cellular stress. These are assembled by the sensory proteins (viz NLRC4, NLRP1, NLRP3, and AIM-2), adaptor protein (ASC), and effector molecule procaspase-1. In NLRP3-mediated inflammasome activation, ASC acts as a mediator between NLRP3 and procaspase-1 for the transmission of signals. A series of homotypic protein-protein interactions (NLRP3 :ASC and ASC :CASP1 ) propagates the downstream signaling for the production of proinflammatory cytokines. Pyrin-only protein 1 (POP1) is known to act as the regulator of inflammasome. It modulates the ASC-mediated inflammasome assembly by interacting with pyrin domain (PYD) of ASC. However, despite similar electrostatic surface potential, the interaction of POP1 with NLRP3 is obscured till date. Herein, to explore the possible PYD-PYD interactions between NLRP3 and POP1, a combined approach of protein-protein docking and molecular dynamics simulation was adapted. The current study revealed that POP1's type-Ia interface and type-Ib interface of NLRP3 might be crucial for 1:1 PYD-PYD interaction. In addition to type-I mode of interaction, we also observed type-II and type-III interaction modes in two different dynamically stable heterotrimeric complexes (POP1-NLRP3-NLRP3 and POP1-NLRP3-POP1). The inter-residual/atomic distance calculation exposed several critical residues that possibly govern the said interaction, which need further investigation. Overall, the findings of this study will shed new light on hitherto concealed molecular mechanisms underlying NLRP3-mediated inflammasome, which will have strong future therapeutic implications.

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Section: Discussionmentioning

confidence: 78%

POP1 might be recruiting its type‐Ia interface for NLRP3‐mediated PYD‐PYD interaction: Insights from MD simulation

Maharana

Vats

Gautam

et al. 2017

J of Molecular Recognition

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“…Research underscores the vital role of macrophages in inflammation, where the intracellular inflammatory pathway serves as the first line of defense for the innate immune system. Pyroptosis, a form of cell death dependent on caspase‐1 produced by infected macrophages, leads to changes in membrane permeability and nuclear condensation 19–21 . Currently, various mechanisms for PROM have been proposed.…”

Section: Discussionmentioning

confidence: 99%

“…Pyroptosis, a form of cell death dependent on caspase‐1 produced by infected macrophages, leads to changes in membrane permeability and nuclear condensation. 19 , 20 , 21 Currently, various mechanisms for PROM have been proposed. These encompass physical damage, infections in the reproductive tract, insufficient presence of trace elements, heightened expression of metalloproteinases, and the programmed cell death of fetal membrane cells, known as apoptosis.…”

Section: Discussionmentioning

confidence: 99%

A study on the level of NLRP3 inflammasome in patients with premature rupture of membranes

Xue,

Wang,

Tao

et al. 2023

Immunity Inflam & Disease

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ObjectiveIn this study, we investigated the levels of interleukin‐1β (IL‐1β), IL‐18, and the NOD‐like receptor pyrin domain‐containing 3 (NLRP3) inflammasome in patients with premature rupture of membranes (PROMs).MethodsWe selected 60 pregnant women at the Fourth Hospital of Baotou between January 2019 and July 2021. These women were divided into three distinct groups: the preterm PROM group with 20 cases, term PROM (TPROM) group with 20 cases, and a control group with 20 cases consisting of normal full‐term pregnancies without PROM. Peripheral blood was collected from all participants. Using enzyme‐linked immunosorbent assay, the levels of IL‐1 and IL‐18 in the plasma were assessed. Additionally, the proportions of NLRP3, apoptosis‐associated speck‐like protein (ASC), and caspase‐1‐positive macrophages were also evaluated.ResultsThe ratios of NLRP3, ASC, IL‐1β, and IL‐18 concentrations, along with the presence of caspase‐1‐positive macrophages, were notably greater in the PROM groups in comparison with the control group (p < .05). In the TPROM group and control group, the proportions of IL‐1β and IL‐18 levels were found to be lower than NLRP3, ASC, and caspase‐1‐positive macrophages levels (p < .05).ConclusionThe concentrations of IL‐1β and IL‐18, as well as the ratios of NLRP3, ASC, and caspase‐1‐positive macrophages, were elevated in patients with PROM compared to the control group. This suggests a potential correlation between the excessive activation of NLRP3 and the development of PROM.

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“…Ligand binding simply shifts the distribution of the populations of each conformer. The conformer selected initially may not have the lowest energy; however, in the bound form it will be the most stable which will result in a “population shift” toward this conformer. − Pre-existing equilibrium model is supported by several experimental studies including nuclear magnetic resonance (NMR) relaxation and single-molecule experiments. − These techniques provide strong evidence about the conformational ensemble dynamics of several proteins including RNase, ,, adenylate kinase (ADK), , calmodulin, − and cyclophilin A . Interestingly, an IgE antibody Spe7 was found to coexist as two distinct substates (conformers) in its native state where each conformer was bound to a different ligand.…”

Section: Introductionmentioning

confidence: 99%

Relation between Protein Intrinsic Normal Mode Weights and Pre-Existing Conformer Populations

et al. 2017

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Intrinsic fluctuations of a protein enable it to sample a large repertoire of conformers including the open and closed forms. These distinct forms of the protein called conformational substates pre-exist together in equilibrium as an ensemble independent from its ligands. The role of ligand might be simply to alter the equilibrium toward the most appropriate form for binding. Normal mode analysis is proved to be useful in identifying the directions of conformational changes between substates. In this study, we demonstrate that the ratios of normalized weights of a few normal modes driving the protein between its substates can give insights about the ratios of kinetic conversion rates of the substates, although a direct relation between the eigenvalues and kinetic conversion rates or populations of each substate could not be observed. The correlation between the normalized mode weight ratios and the kinetic rate ratios is around 83% on a set of 11 non-enzyme proteins and around 59% on a set of 17 enzymes. The results are suggestive that mode motions carry intrinsic relations with thermodynamics and kinetics of the proteins.

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Conformation switching of AIM2 PYD domain revealed by NMR relaxation and MD simulation

Cited by 8 publications

References 27 publications

POP1 might be recruiting its type‐Ia interface for NLRP3‐mediated PYD‐PYD interaction: Insights from MD simulation

POP1 might be recruiting its type‐Ia interface for NLRP3‐mediated PYD‐PYD interaction: Insights from MD simulation

A study on the level of NLRP3 inflammasome in patients with premature rupture of membranes

Relation between Protein Intrinsic Normal Mode Weights and Pre-Existing Conformer Populations

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