Structural basis of TRPV1 modulation by endogenous bioactive lipids

Arnold, William R.; Julius, David; Cheng, Yifan

doi:10.1101/2023.05.11.540281

Cited by 3 publications

(2 citation statements)

References 45 publications

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“…Determining the functional role of CL within the structural framework of intact lipid bilayers poses challenges due to the heterogeneity and dynamic nature of mitochondrial membranes. Prior research has demonstrated that brominated and iodinated lipids behave similarly to their native counterparts and can serve as contrast-enhancing probes to delineate specific lipids within membranes (54,55). Moreover, the utilization of bromo-substituents on aliphatic double bounds has a well-established history as fluorescence quenchers in model membranes (57)(58)(59).…”

Section: Discussionmentioning

confidence: 99%

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Cardiolipin clustering promotes mitochondrial membrane dynamics

Zuccaro,

Abriata,

Meireles

et al. 2024

Preprint

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Cardiolipin (CL) is a mitochondria-specific phospholipid that forms heterotypic interactions with membrane-shaping proteins and regulates the dynamic remodeling and function of mitochondria. However, the precise mechanisms through which CL influences mitochondrial morphology are not well understood. In this study, employing molecular dynamics (MD) simulations, we observed CL localize near the membrane-binding sites of the mitochondrial fusion protein Optic Atrophy 1 (OPA1). To validate these findings experimentally, we developed a bromine-labeled CL probe to enhance cryoEM contrast and characterize the structure of OPA1 assemblies bound to the CL-brominated lipid bilayers. Our images provide direct evidence of interactions between CL and two conserved motifs within the paddle domain (PD) of OPA1, which control membrane-shaping mechanisms. We further observed a decrease in membrane remodeling activity for OPA1 in lipid compositions with increasing concentrations of monolyso-cardiolipin (MLCL). Suggesting that the partial replacement of CL by MLCL accumulation, as observed in Barth syndrome-associated mutations of the tafazzin phospholipid transacylase, compromises the stability of protein-membrane interactions. Our analyses provide insights into how biological membranes regulate the mechanisms governing mitochondrial homeostasis.

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Section: Discussionmentioning

confidence: 99%

“…3A and fig. S5) (54,55). We reconstituted human S-OPA1 onto lipid bilayers (both vesicles and nanotubes) containing brominated CL and learned that S-OPA1 can self-organize into higher-order structures on these bilayers and induce the protrusions of narrow lipid tubes (fig.…”

Section: Structure Of S-opa1 Assembly Bound To Membranes Containing C...mentioning

confidence: 99%

Cardiolipin clustering promotes mitochondrial membrane dynamics

Zuccaro,

Abriata,

Meireles

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

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Conservation of the cooling agent binding pocket within the TRPM subfamily

Huffer,

Denley,

Oskoui

et al. 2024

eLife

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Transient Receptor Potential (TRP) channels are a large and diverse family of tetrameric cation selective channels that are activated by many different types of stimuli, including noxious heat or cold, organic ligands such as vanilloids or cooling agents, or intracellular Ca 2+ . Structures available for all subtypes of TRP channels reveal that the transmembrane domains are closely related despite their unique sensitivity to activating stimuli. Here we use computational and electrophysiological approaches to explore the conservation of the cooling agent binding pocket identified within the S1-S4 domain of the Melastatin subfamily member TRPM8, the mammalian sensor of noxious cold, with other TRPM channel subtypes. We find that a subset of TRPM channels, including TRPM2, TRPM4 and TRPM5, contain well-conserved cooling agent binding pockets. We then show how the cooling agent icilin modulates activation of TRPM4 to intracellular Ca 2+ , enhancing the sensitivity of the channel to Ca 2+ and diminishing outward-rectification to promote opening at negative voltages. Mutations known to promote or diminish activation of TRPM8 by icilin similarly alter activation of TRPM4 by the cooling agent, suggesting that icilin binds to the cooling agent binding pocket to promote opening of the channel. These findings demonstrate that TRPM4 and TRPM8 channels share related cooling agent binding pockets that are allosterically coupled to opening of the pore.

show abstract

Conservation of the cooling agent binding pocket within the TRPM subfamily

Huffer,

Denley,

Oskoui

et al. 2024

eLife

View full text Add to dashboard Cite

Transient receptor potential (TRP) channels are a large and diverse family of tetrameric cation-selective channels that are activated by many different types of stimuli, including noxious heat or cold, organic ligands such as vanilloids or cooling agents, or intracellular Ca2+. Structures available for all subtypes of TRP channels reveal that the transmembrane domains are closely related despite their unique sensitivity to activating stimuli. Here, we use computational and electrophysiological approaches to explore the conservation of the cooling agent binding pocket identified within the S1–S4 domain of the Melastatin subfamily member TRPM8, the mammalian sensor of noxious cold, with other TRPM channel subtypes. We find that a subset of TRPM channels, including TRPM2, TRPM4, and TRPM5, contain pockets very similar to the cooling agent binding pocket in TRPM8. We then show how the cooling agent icilin modulates activation of mouse TRPM4 to intracellular Ca2+, enhancing the sensitivity of the channel to Ca2+ and diminishing outward-rectification to promote opening at negative voltages. Mutations known to promote or diminish activation of TRPM8 by cooling agents similarly alter activation of TRPM4 by icilin, suggesting that icilin binds to the cooling agent binding pocket to promote opening of the channel. These findings demonstrate that TRPM4 and TRPM8 channels share related ligand binding pockets that are allosterically coupled to opening of the pore.

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Structural basis of TRPV1 modulation by endogenous bioactive lipids

Cited by 3 publications

References 45 publications

Cardiolipin clustering promotes mitochondrial membrane dynamics

Cardiolipin clustering promotes mitochondrial membrane dynamics

Conservation of the cooling agent binding pocket within the TRPM subfamily

Conservation of the cooling agent binding pocket within the TRPM subfamily

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