The proposed channel-enzyme transient receptor potential melastatin 2 does not possess ADP ribose hydrolase activity

Iordanov, I; Mihályi, Csaba; Tóth, Balázs; Csanády, László

doi:10.7554/elife.17600

Cited by 52 publications

(70 citation statements)

References 40 publications

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“…However, subsequent studies have since repudiated this mechanism, as the NUDT9H domain lacks enzymatic activity. Instead it has been suggested that the NUDT9H domain merely serves as a binding site for ADPR 20 .…”

Section: Mainmentioning

confidence: 99%

“…Functional studies have shown that the interaction between the core subdomain of NUDT9H and the rest of the channel is important for stabilizing an open state of the TRPM2 channel, underscoring the importance of this secondary interface in channel opening 20 . Strikingly, our TRPM2 DR_Ca2+ structure adopts a combination of the two distinct interactions associated with the NUDT9H domain and the neighboring MHRs.…”

Section: Alternating Quaternary Structure Rearrangement In the Bottommentioning

confidence: 99%

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Visualizing structural transitions of ligand-dependent gating of the TRPM2 channel

Yin

Hsu

et al. 2019

Preprint

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The calcium-permeable transient receptor potential melastatin 2 (TRPM2) channel plays a key role in redox sensation in many cell types 1-3 . Channel activation requires binding of both ADP-ribose (ADPR) 2,4-6 and Ca 2+ 7 . The recently published TRPM2 structures from Danio rerio in the ligand-free and in the ADPR/Ca 2+ -bound conditions represent the channel in closed and open states, which uncover substantial tertiary and quaternary conformational rearrangements 8 .However, it is unclear how these rearrangements occur within the tetrameric channel during channel gating. Here we report two cryo-electron microscopy structures of TRPM2 from the same species in complex with Ca 2+ alone, and with both ADPR and Ca 2+ , determined to an overall resolution of ~3.8 Å and ~4.2 Å respectively. In comparison with the published results, our studies capture TRPM2 in two-fold symmetric intermediate states, offering a glimpse of the structural transitions within the tetramer that bridge the closed and open conformations.3 MainThe transient receptor potential melastatin (TRPM) ion channel family is part of the TRP channel superfamily and comprises eight members (TRPM1 to TRPM8) that carry out diverse functions in a variety of physiological pathways 9 . TRPM2 is a calcium-permeable non-selective cation channel that is widely expressed in the nervous, immune, and endocrine systems, and plays a crucial role in warmth and redox-dependent signaling 1-3 . Studies of TRPM2-deficient mice have shown that TRPM2 channels expressed in sensory and central neurons are responsible for sensation of warm temperatures and body temperature regulation 10,11 . TRPM2 has also been found to be activated by reactive oxygen species (ROS), consequently playing a key role in Ca 2+ signaling involved in chemokine production, insulin production, and cell death under oxidative stress [12][13][14][15][16] .Extensive electrophysiological studies have shown that activation of TRPM2 by ROS is caused by an increase of intracellular ADP-ribose (ADPR), a TRPM2 agonist, and that both ADPR and Ca 2+ are required for channel activation 2,[4][5][6][7]17 . Notably, TRPM2 contains a putative enzyme domain, called the Nudix Hydrolase 9 Homology (NUDT9H) domain located at the C-terminus, which exhibits a high degree of homology to the mitochondrial ADP-ribose pyrophosphatase NUDT9 18,19 . As such, TRPM2 was initially classified as a channel-enzyme in which enzymatic activity was believed to be coupled to channel gating 2,18 . However, subsequent studies have since repudiated this mechanism, as the NUDT9H domain lacks enzymatic activity. Instead it has been suggested that the NUDT9H domain merely serves as a binding site for ADPR 20 .Recently, structures of the zebrafish Danio rerio TRPM2 were reported in the ligand-free closed state and in the ADPR/Ca 2+ -bound open state (hereafter referred to as TRPM2 DR_closed and TRPM2 DR_open respectively) 8 . This study not only revealed the location of the NUDT9H domain, but also showed that the Ca 2+ ion binds in the cavity formed...

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Section: Mainmentioning

confidence: 99%

Section: Alternating Quaternary Structure Rearrangement In the Bottommentioning

confidence: 99%

Visualizing structural transitions of ligand-dependent gating of the TRPM2 channel

Yin

Hsu

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Cyclic ADPR indirectly activates TRPM2 channels in a similar manner 55 . Interestingly, the NUDT9-H domain of TRPM2 channels has slow hydrolytic kinetics, thus it is likely involved in ADPR binding and channel gating, rather than ADPR hydrolysis 51, 56, 57 , as opposed to the homologous mitochondrial pyrophosphatase NUDIT9 57 . ADPR-induced gating of TRPM2 requires co-binding of Ca 2+ 58 , suggesting that the channel acts as a co-incidence detector of upstream signaling events involving increases in intracellular [Ca 2+ ] and generation of ADPR.…”

Section: Redox Regulation Of Trpm2mentioning

confidence: 99%

“…54 Cyclic ADPR indirectly activates TRPM2 channels in a similar manner. 55 Interestingly, the NUDT9-H domain of TRPM2 channels has slow hydrolytic kinetics; thus, it is likely involved in ADPR binding and channel gating, rather than ADPR hydrolysis, 51,56,57 as opposed to the homologous mitochondrial pyrophosphatase NUDIT9. 57 This study also linked TRPM2 activity to a reduction in transendothelial electrical resistance in cultured monolayers treated with H 2 O 2 , F I G U R E 2 Redox modifications of TRP channel activity.…”

Section: Redox Regulation Of Trpm2mentioning

confidence: 99%

Redox regulation of transient receptor potential channels in the endothelium

Pires

Earley

2017

Microcirculation

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Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important mediators of signaling pathways in the endothelium. Specific members of the transient receptor potential (TRP) superfamily of cation channels act as important Ca2+ influx pathways in endothelial cells, and are involved in endothelium-dependent vasodilation, regulation of barrier permeability, and angiogenesis. ROS and RNS can modulate the activity of certain TRP channels mainly by modifying specific cysteine residues or by stimulating the production of second messengers. In this review we highlight the recent literature describing in redox regulation of TRP channel activity in endothelial cells as well as the physiological importance of these pathways and implication for cardiovascular diseases.

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“…For example, pyrophosphohydrolases are now known to cleave ADP‐ribose (yielding adenosine 5′‐monophosphate and ribose 5‐phosphate) . Recent studies indicate a broad swath of cellular roles for ADP‐ribose, including chromatin remodeling, membrane protein ion channel gating, and a host of processes dependent upon ADP‐ribosylation; this suggests that Nudix ADP‐ribose pyrophosphohydrolases may play roles in many physiological contexts. Other hydrolases are involved in eukaryotic and bacterial mRNA decapping by recognizing either the 5′‐7‐methylguanosine or the NAD mRNA cap, respectively, initiating the process of mRNA degradation .…”

Section: Introductionmentioning

confidence: 99%

The evolution of function within the Nudix homology clan

Srouji

Park

et al. 2017

Proteins

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The Nudix homology clan encompasses over 80,000 protein domains from all three domains of life, defined by homology to each other. Proteins with a domain from this clan fall into four general functional classes: pyrophosphohydrolases, isopentenyl diphosphate isomerases (IDIs), adenine/guanine mismatch-specific adenine glycosylases (A/G-specific adenine glycosylases), and non-enzymatic activities such as protein/protein interaction and transcriptional regulation. The largest group, pyrophosphohydrolases, encompasses more than 100 distinct hydrolase specificities. To understand the evolution of this vast number of activities, we assembled and analyzed experimental and structural data for 205 Nudix proteins collected from the literature. We corrected erroneous functions or provided more appropriate descriptions for 53 annotations described in the Gene Ontology Annotation database in this family, and propose 275 new experimentally-based annotations. We manually constructed a structure-guided sequence alignment of 78 Nudix proteins. Using the structural alignment as a seed, we then made an alignment of 347 “select” Nudix homology domains, curated from structurally determined, functionally characterized, or phylogenetically important Nudix domains. Based on our review of Nudix pyrophosphohydrolase structures and specificities, we further analyzed a loop region downstream of the Nudix hydrolase motif previously shown to contact the substrate molecule and possess known functional motifs. This loop region provides a potential structural basis for the functional radiation and evolution of substrate specificity within the hydrolase family. Finally, phylogenetic analyses of the 347 select protein domains and of the complete Nudix homology clan revealed general monophyly with regard to function and a few instances of probable homoplasy.

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The proposed channel-enzyme transient receptor potential melastatin 2 does not possess ADP ribose hydrolase activity

Cited by 52 publications

References 40 publications

Visualizing structural transitions of ligand-dependent gating of the TRPM2 channel

Visualizing structural transitions of ligand-dependent gating of the TRPM2 channel

Redox regulation of transient receptor potential channels in the endothelium

The evolution of function within the Nudix homology clan

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