Photoswitchable Lipids

Morstein, Johannes; Impastato, Anna C.; Trauner, Dirk

doi:10.1002/cbic.202000449

Cited by 69 publications

(77 citation statements)

References 62 publications

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“…Mass-spectrometry-based lipidomics has unearthed previously unidentified lipids including signaling molecules such as fatty acid esters of hydroxy fatty acids (FAHFAs), which regulate insulin sensitivity [89,90]. Chemical probes including photoswitches have the capacity to functionally characterize lipids and the proteins they interact with, while photocleavable groups can facilitate the temporal range of lipid activity [91]. Labels including fluorescent tags such as Bodipy and GFP as well as luminescent tags on acyl-chains provide imaging potential to determine cellular localization and lipid uptake [92][93][94].…”

Section: Perspectivesmentioning

confidence: 99%

Mitochondrial Lipid Signaling and Adaptive Thermogenesis

et al. 2021

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Thermogenesis is an energy demanding process by which endotherms produce heat to maintain their body temperature in response to cold exposure. Mitochondria in the brown and beige adipocytes play a key role in thermogenesis, as the site for uncoupling protein 1 (UCP1), which allows for the diffusion of protons through the mitochondrial inner membrane to produce heat. To support this energy demanding process, the mitochondria in brown and beige adipocytes increase oxidation of glucose, amino acids, and lipids. This review article explores the various mitochondria-produced and processed lipids that regulate thermogenesis including cardiolipins, free fatty acids, and acylcarnitines. These lipids play a number of roles in thermogenic adipose tissue including structural support of UCP1, transcriptional regulation, fuel source, and activation of cell signaling cascades.

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Section: Perspectivesmentioning

confidence: 99%

Mitochondrial Lipid Signaling and Adaptive Thermogenesis

et al. 2021

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“…Photoswitchable lipids allow for the optical control of lipid function with high spatiotemporal resolution, enabling precise functional manipulations. They have been shown to modulate many aspects of membrane biophysics, including permeability, fluidity, lipid mobility and domain formation (47–49). Recently, photoswitchable sphingolipids have emerged as potent tools to investigate cellular physiology using optical control, including receptor-mediated signaling and immune function (50–53).…”

Section: Resultsmentioning

confidence: 99%

Cholesterol and sphingomyelin are critical for Fcγ receptor-mediated phagocytosis of Cryptococcus neoformans by macrophages

Bryan

You

et al. 2021

Preprint

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Cryptococcus neoformans is a fungal pathogen that causes life-threatening meningoencephalitis in lymphopenic patients. Pulmonary macrophages comprise the first line of host defense upon inhalation of fungal spores, whereby macrophages either aid in clearance or serve as a niche for its dissemination. Given that macrophages play a key role in the outcome of a cryptococcal infection, it is crucial to understand factors that mediate phagocytosis of C. neoformans. Since lipid rafts (high order plasma membrane domains enriched in cholesterol and sphingomyelin) have been implicated in facilitating phagocytosis, we evaluated whether these ordered domains govern macrophages’ ability to phagocytose C. neoformans. We found that cholesterol or sphingomyelin depletion resulted in significantly deficient IgG-mediated phagocytosis of the fungus. Moreover, repletion of macrophage cells with a raft-promoting sterol (7-dehydrocholesterol) rescued this phagocytic deficiency while a raft-inhibiting sterol (coprostanol) significantly decreased IgG-mediated phagocytosis of C. neoformans. Using a photoswitchable sphingomyelin (AzoSM), we observed that the raft-promoting conformation (trans-AzoSM) resulted in efficient phagocytosis whereas raft-inhibiting conformation (cis-AzoSM) significantly blunted phagocytosis in a reversible manner. We observed that the effect on phagocytosis may be mediated by facilitating Fcγ receptor (FcγR) function, whereby IgG immune complexes cross-link to FcγRIII, resulting in tyrosine phosphorylation of FcR γ-subunit (FcRγ), an important accessory protein in the FcγR signaling cascade. Correspondingly, cholesterol or sphingomyelin depletion resulted in decreased FcRγ phosphorylation. Repletion with 7-dehydrocholesterol restored phosphorylation, whereas repletion with coprostanol showed FcRγ phosphorylation comparable to unstimulated cells. Together, these data suggest that lipid rafts are critical for facilitating FcγRIII-mediated phagocytosis of C. neoformans.

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“…Hand in hand with these computational advancements, the toolkit of available photoswitchable ligands is rapidly expanding. The development of photoswitchable amino acids [ 82 ] and lipids [ 145 ] opens new avenues to investigate ion channel regulatory mechanisms. MD simulations are expected to be particularly useful to characterize at the molecular level the effect of these novel photoswitchable molecules [ 42 , 78 , 146 , 147 ].…”

Section: Conclusion and Perspectivesmentioning

confidence: 99%

Photopharmacology of Ion Channels through the Light of the Computational Microscope

Nin‐Hill

Mueller

Molteni

et al. 2021

IJMS

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The optical control and investigation of neuronal activity can be achieved and carried out with photoswitchable ligands. Such compounds are designed in a modular fashion, combining a known ligand of the target protein and a photochromic group, as well as an additional electrophilic group for tethered ligands. Such a design strategy can be optimized by including structural data. In addition to experimental structures, computational methods (such as homology modeling, molecular docking, molecular dynamics and enhanced sampling techniques) can provide structural insights to guide photoswitch design and to understand the observed light-regulated effects. This review discusses the application of such structure-based computational methods to photoswitchable ligands targeting voltage- and ligand-gated ion channels. Structural mapping may help identify residues near the ligand binding pocket amenable for mutagenesis and covalent attachment. Modeling of the target protein in a complex with the photoswitchable ligand can shed light on the different activities of the two photoswitch isomers and the effect of site-directed mutations on photoswitch binding, as well as ion channel subtype selectivity. The examples presented here show how the integration of computational modeling with experimental data can greatly facilitate photoswitchable ligand design and optimization. Recent advances in structural biology, both experimental and computational, are expected to further strengthen this rational photopharmacology approach.

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Photoswitchable Lipids

Cited by 69 publications

References 62 publications

Mitochondrial Lipid Signaling and Adaptive Thermogenesis

Mitochondrial Lipid Signaling and Adaptive Thermogenesis

Cholesterol and sphingomyelin are critical for Fcγ receptor-mediated phagocytosis of Cryptococcus neoformans by macrophages

Photopharmacology of Ion Channels through the Light of the Computational Microscope

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