Structure of a TRPM2 channel in complex with Ca2+ explains unique gating regulation

Zhang, Zhe; Tóth, Balázs; Szöllősi, András; Chen, Jue; Csanády, László

doi:10.7554/elife.36409

Cited by 118 publications

(205 citation statements)

References 52 publications

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“…1c). Similar to the previously reported TRPM2, TRPM4, and TRPM8 structures 8,[26][27][28][29][30][31] , each TRPM2 DR protomer contains an N-terminal region composed of MHR1 to MHR4, a transmembrane channel region, and a C-terminal region. The CC2 serves as a link between the C-terminal NUDT9H domain and the rest of the channel (Fig.…”

Section: Structure Determination and Overall Architecture Of Trpm2 Drsupporting

confidence: 82%

“…Like other published TRP channel structures, the TMD layer adopts a domain-swapped configuration between the VSLD and the pore 24,25 . Consistent with the previously reported TRPM2 structures 8,26,27 , we also identified a Ca 2+ binding site located in the cavity formed by the VSLD in the TRPM2 DR_Ca2+ and 6 TRPM2 DR_ADPR/Ca2+ structures ( Supplementary Fig. 6a-c).…”

supporting

confidence: 91%

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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: Structure Determination and Overall Architecture Of Trpm2 Drsupporting

confidence: 82%

supporting

confidence: 91%

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

Yin

Hsu

et al. 2019

Preprint

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“…Other than hs TRPM2, structures of zebrafish TRPM2 ( dr TRPM2) and sea anemone TRPM2 ( nv TRPM2) have been solved, revealing a gating mechanism similar to hs TRPM2 with some important differences . The structure of nv TRPM2 was determined in complex with Ca 2+ , while the structures of dr TRPM2 contain states – the apo state, in complex with Ca 2+ , and in complex with Ca 2+ and ADPR.…”

Section: Structures and Gating Mechanisms Of Trpm2 In Other Speciesmentioning

confidence: 99%

“…In both structures, Ca 2+ is coordinated by residues in VSLD helices S2 and S3 (Fig. A) . However, symmetry differs between the two Ca 2+ ‐bound structures, with nv TRPM2 adopting a fourfold symmetric architecture whereas dr TRPM2 a twofold symmetric intermediate state obvious in the MHR1/2 and MHR3 domains.…”

Section: Structures and Gating Mechanisms Of Trpm2 In Other Speciesmentioning

confidence: 99%

“…However, the structures of these channels were obtained in closed, inactive states, leaving their gating mechanisms unclear. Recently, structures of human ( hs ), zebrafish ( dr ), and sea anemone ( nv ) TRPM2 in different conformational states were solved, from which gating mechanisms of TRPM2 have been proposed . Together, these TRPM2 structures not only provide an understanding on species‐specific contributions of the NUDT9H domain to channel activation, but also highlight an allosteric propagation mechanism that integrates cytoplasmic signals and local conformational changes at the transmembrane (TM) region to enlarge the ion permeation pore.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of TRPM2 channel gating revealed by cryo‐EM

Xia

Wang

et al. 2019

The FEBS Journal

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Transient receptor potential melastatin 2 (TRPM2) is a non‐selective cation channel that allows Ca2+ influx across the plasma membrane and efflux from lysosomes upon opening. TRPM2 is best known as a biosensor of reactive oxygen species (ROS), which mediates some of the body's responses to oxidative stress. As such, TRPM2 is involved in a plethora of biological processes including immune response, insulin secretion, body temperature control and neuronal cell death, and represents an emerging therapeutic target for many human diseases, from diabetes to inflammatory and neurodegenerative diseases. A direct ligand of TRPM2 is ADP‐ribose (ADPR), which accumulates in cells at high levels of ROS, and activates TRPM2 synergistically with intracellular calcium (Ca2+). Here, we describe recent cryo‐electron microscopy (cryo‐EM) structures of TRPM2 and summarize the insights they provided into the gating mechanism of the channel.

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Enzymatic and Endogenous Synthesis of Nad(p)‐derived Calcium‐mobilizing Messengers

Lee¹,

Zhao²

2022

Nucleic Acids in Medicinal Chemistry and Chemical Biology

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Structure of a TRPM2 channel in complex with Ca2+ explains unique gating regulation

Cited by 118 publications

References 52 publications

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

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

Mechanism of TRPM2 channel gating revealed by cryo‐EM

Enzymatic and Endogenous Synthesis of Nad(p)‐derived Calcium‐mobilizing Messengers

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