Structural mechanism of heat-induced opening of a temperature-sensitive TRP channel

Nadezhdin, Kirill D.; Neuberger, Arthur; Trofimov, Yu. A.; Крылов, Н. А.; Sinica, Viktor; Kupko, Nikita; Vlachová, Viktorie; Zakharian, Eleonora; Efremov, Roman G.; Sobolevsky, Alexander I.

doi:10.1038/s41594-021-00615-4

Cited by 87 publications

(149 citation statements)

References 79 publications

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“…Recent structures of TRPV3 in NW11 asolectin nanodiscs at different temperatures illuminate the mechanism of heat activation of TRPV3. The closed structure shows a phospholipid in this site that is excluded from this pocket by a conformational change in the heat-activated open structure (Nadezhdin et al, 2021), similar to the state-dependence of PI binding in TRPV1. MD simulations suggest that this pocket is relatively non-selective for different glycerophospholipids (PI, PC, PS, and PE), and is less favorable for cholesterol (Nadezhdin et al, 2021).…”

Section: Vanilloid Binding Sitementioning

confidence: 67%

“…The closed structure shows a phospholipid in this site that is excluded from this pocket by a conformational change in the heat-activated open structure (Nadezhdin et al, 2021), similar to the state-dependence of PI binding in TRPV1. MD simulations suggest that this pocket is relatively non-selective for different glycerophospholipids (PI, PC, PS, and PE), and is less favorable for cholesterol (Nadezhdin et al, 2021). In contrast, structures of TRPV6 and TRPV3 in MSP2N2 asolectin nanodiscs show a phospholipid density in this site in activated conformations with loss of the lipid in the closed conformations, suggesting a mechanism whereby lipids may be agonists or positive allosteric modulators of these channels (McGoldrick et al, 2018;Deng et al, 2020).…”

Section: Vanilloid Binding Sitementioning

confidence: 67%

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Druggable Lipid Binding Sites in Pentameric Ligand-Gated Ion Channels and Transient Receptor Potential Channels

2022

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Lipids modulate the function of many ion channels, possibly through direct lipid-protein interactions. The recent outpouring of ion channel structures by cryo-EM has revealed many lipid binding sites. Whether these sites mediate lipid modulation of ion channel function is not firmly established in most cases. However, it is intriguing that many of these lipid binding sites are also known sites for other allosteric modulators or drugs, supporting the notion that lipids act as endogenous allosteric modulators through these sites. Here, we review such lipid-drug binding sites, focusing on pentameric ligand-gated ion channels and transient receptor potential channels. Notable examples include sites for phospholipids and sterols that are shared by anesthetics and vanilloids. We discuss some implications of lipid binding at these sites including the possibility that lipids can alter drug potency or that understanding protein-lipid interactions can guide drug design. Structures are only the first step toward understanding the mechanism of lipid modulation at these sites. Looking forward, we identify knowledge gaps in the field and approaches to address them. These include defining the effects of lipids on channel function in reconstituted systems using asymmetric membranes and measuring lipid binding affinities at specific sites using native mass spectrometry, fluorescence binding assays, and computational approaches.

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Section: Vanilloid Binding Sitementioning

confidence: 67%

Section: Vanilloid Binding Sitementioning

confidence: 67%

Druggable Lipid Binding Sites in Pentameric Ligand-Gated Ion Channels and Transient Receptor Potential Channels

2022

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“…In the middle, SDS-PAGE for the protein peak fractions outlined by the red dashed lines on the SEC plot. On the right, normalized FSEC traces for purified At GLR3.4, rat GluA2-γ2 fusion ( Twomey et al., 2016 , 2017 ), mouse TRPV3 ( Nadezhdin et al., 2021 ; Singh et al., 2018 ) and human TRPV6 ( Bhardwaj et al., 2020 ; McGoldrick et al., 2018 ). The latter three membrane proteins represent molecular weight markers and confirm the tetrameric assembly of At GLR3.4.…”

Section: Step-by-step Methods Detailsmentioning

confidence: 99%

Purification and cryo-EM structure determination of Arabidopsis thaliana GLR3.4

et al. 2021

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Summary Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that play crucial roles in the central nervous system. iGluR homologs, termed glutamate receptor-like channels (GLRs), have been found in plants. Investigating the structural and functional relationship between iGluRs and GLRs was limited by GLR protein expression, purification, and structural characterization. Here, we provide a detailed protocol for Arabidopsis thaliana GLR3.4 ( At GLR3.4) expression in a mammalian cell line and purification for structure determination by cryogenic electron microscopy (cryo-EM). For the complete details on the use and execution of this protocol, please refer to Green et al. (2021) .

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“…This is supported by structures of the temperature sensitive, mouse TRPV3 channel which revealed a lipid, likely to be a phospholipid, bound to the vanilloid binding site in the closed state but not in the open state of the protein. Loss of the lipid at the phospholipid binding site is postulated to be key to transition from the closed to the sensitized and ultimately the open state of the channel upon heat-induced activation [92].…”

Section: Channelsmentioning

confidence: 99%

Insights into the Role of Membrane Lipids in the Structure, Function and Regulation of Integral Membrane Proteins

Renard

Byrne

2021

IJMS

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Membrane proteins exist within the highly hydrophobic membranes surrounding cells and organelles, playing key roles in cellular function. It is becoming increasingly clear that the membrane does not just act as an appropriate environment for these proteins, but that the lipids that make up these membranes are essential for membrane protein structure and function. Recent technological advances in cryogenic electron microscopy and in advanced mass spectrometry methods, as well as the development of alternative membrane mimetic systems, have allowed experimental study of membrane protein–lipid complexes. These have been complemented by computational approaches, exploiting the ability of Molecular Dynamics simulations to allow exploration of membrane protein conformational changes in membranes with a defined lipid content. These studies have revealed the importance of lipids in stabilising the oligomeric forms of membrane proteins, mediating protein–protein interactions, maintaining a specific conformational state of a membrane protein and activity. Here we review some of the key recent advances in the field of membrane protein–lipid studies, with major emphasis on respiratory complexes, transporters, channels and G-protein coupled receptors.

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Structural mechanism of heat-induced opening of a temperature-sensitive TRP channel

Cited by 87 publications

References 79 publications

Druggable Lipid Binding Sites in Pentameric Ligand-Gated Ion Channels and Transient Receptor Potential Channels

Druggable Lipid Binding Sites in Pentameric Ligand-Gated Ion Channels and Transient Receptor Potential Channels

Purification and cryo-EM structure determination of Arabidopsis thaliana GLR3.4

Insights into the Role of Membrane Lipids in the Structure, Function and Regulation of Integral Membrane Proteins

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