Architecture of the TRPM2 channel and its activation mechanism by ADP-ribose and calcium

Huang, Yongyang; Winkler, Paige A; Sun, Weinan; Lü, Wei; Du, Juan

doi:10.1038/s41586-018-0558-4

Cited by 152 publications

(296 citation statements)

References 56 publications

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“…Strikingly, upon the engagement of ADPR, the Ca 2+ ‐binding site moves toward the TRP helix H1, shown by the open‐state structures of hs TRPM2 and dr TRPM2 (Fig. B) . The consequence is that Ca 2+ is not only coordinated by the S2 and S3 helices, but also by the TRP H1.…”

Section: Structures and Gating Mechanisms Of Trpm2 In Other Speciesmentioning

confidence: 96%

“…C) . In contrast, the MHR1/2 domain, not the NUDT9H domain, was shown to bind ADPR in dr TRPM2 . Two conserved Arg residues were identified to be critical for ADPR engagement and channel gating in zebrafish TRPM2.…”

Section: Structures and Gating Mechanisms Of Trpm2 In Other Speciesmentioning

confidence: 96%

“…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%

“…3A) . 3B) [21,22]. The consequence is that Ca 2+ is not only coordinated by the S2 and S3 helices, but also by the TRP H1.…”

Section: Calcium-binding Sitesmentioning

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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Section: Structures and Gating Mechanisms Of Trpm2 In Other Speciesmentioning

confidence: 96%

Section: Structures and Gating Mechanisms Of Trpm2 In Other Speciesmentioning

confidence: 96%

Section: Structures and Gating Mechanisms Of Trpm2 In Other Speciesmentioning

confidence: 99%

“…3A) . 3B) [21,22]. The consequence is that Ca 2+ is not only coordinated by the S2 and S3 helices, but also by the TRP H1.…”

Section: Calcium-binding Sitesmentioning

confidence: 99%

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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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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Identification of Ligands for Ion Channels: TRPM2

Gu,

Liu,

et al. 2024

ChemBioChem

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Transient receptor potential melastatin 2 (TRPM2) is a calcium‐permeable, nonselective cation channel with a widespread distribution throughout the body. It is involved in many pathological and physiological processes, making it a potential therapeutic target for various diseases, including Alzheimer's disease, Parkinson’s disease, and cancers. New analytical techniques are beneficial for gaining a deeper understanding of its involvement in disease pathogenesis and for advancing the drug discovery for TRPM2‐related diseases. In this work, we present the application of collision‐induced affinity selection mass spectrometry (CIAS‐MS) for the direct identification of ligands binding to TRPM2. CIAS‐MS circumvents the need for high mass detection typically associated with mass spectrometry of large membrane proteins. Instead, it focuses on the detection of small molecules dissociated from the ligand‐protein‐detergent complexes. This affinity selection approach consolidates all affinity selection steps within the mass spectrometer, resulting in a streamlined process. We showed the direct identification of a known TRPM2 ligand dissociated from the protein‐ligand complex. We demonstrated that CIAS‐MS can identify binding ligands from complex mixtures of compounds and screened a compound library against TRPM2. We investigated the impact of voltage increments and ligand concentrations on the dissociation behavior of the binding ligand, revealing a dose‐dependent relationship.

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Architecture of the TRPM2 channel and its activation mechanism by ADP-ribose and calcium

Cited by 152 publications

References 56 publications

Mechanism of TRPM2 channel gating revealed by cryo‐EM

Mechanism of TRPM2 channel gating revealed by cryo‐EM

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

Identification of Ligands for Ion Channels: TRPM2

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