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3. Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy

Author

Hu, Jiong, Dziumbla, Sarah, Lin, Jihong, Bibli, Sofia-Iris, Zukunft, Sven, de Mos, Julian, Awwad, Khader, Frömel, Timo, Jungmann, Andreas, Devraj, Kavi, Cheng, Zhixing, Wang, Liya, Fauser, Sascha, Eberhart, Charles G, Sodhi, Akrit, Hammock, Bruce D, Liebner, Stefan, Müller, Oliver J, Glaubitz, Clemens, Hammes, Hans-Peter, Popp, Rüdiger, and Fleming, Ingrid

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Diabetes, Eye Disease and Disorders of Vision, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, Metabolic and endocrine, Animals, Antigens, CD, Cadherins, Capillary Permeability, Carrier Proteins, Cell Membrane, Cell Movement, Cell Survival, Diabetic Retinopathy, Disease Models, Animal, Disease Progression, Docosahexaenoic Acids, Endothelial Cells, Ependymoglial Cells, Epoxide Hydrolases, Fatty Acids, Unsaturated, Female, Humans, Intercellular Junctions, Male, Mice, Mice, Inbred C57BL, Pancreatic Elastase, Pericytes, Presenilin-1, Retina, Solubility, Vitreous Body, General Science & Technology
Abstract

Diabetic retinopathy is an important cause of blindness in adults, and is characterized by progressive loss of vascular cells and slow dissolution of inter-vascular junctions, which result in vascular leakage and retinal oedema. Later stages of the disease are characterized by inflammatory cell infiltration, tissue destruction and neovascularization. Here we identify soluble epoxide hydrolase (sEH) as a key enzyme that initiates pericyte loss and breakdown of endothelial barrier function by generating the diol 19,20-dihydroxydocosapentaenoic acid, derived from docosahexaenoic acid. The expression of sEH and the accumulation of 19,20-dihydroxydocosapentaenoic acid were increased in diabetic mouse retinas and in the retinas and vitreous humour of patients with diabetes. Mechanistically, the diol targeted the cell membrane to alter the localization of cholesterol-binding proteins, and prevented the association of presenilin 1 with N-cadherin and VE-cadherin, thereby compromising pericyte-endothelial cell interactions and inter-endothelial cell junctions. Treating diabetic mice with a specific sEH inhibitor prevented the pericyte loss and vascular permeability that are characteristic of non-proliferative diabetic retinopathy. Conversely, overexpression of sEH in the retinal Müller glial cells of non-diabetic mice resulted in similar vessel abnormalities to those seen in diabetic mice with retinopathy. Thus, increased expression of sEH is a key determinant in the pathogenesis of diabetic retinopathy, and inhibition of sEH can prevent progression of the disease.

Published
2017

9. Probing the Conformational Space of the Cannabinoid Receptor 2 and a Systematic Investigation of DNP-Enhanced MAS NMR Spectroscopy of Proteins in Detergent Micelles

Author

Becker-Baldus, Johanna, primary, Yeliseev, Alexei, additional, Joseph, Thomas T., additional, Sigurdsson, Snorri Th., additional, Zoubak, Lioudmila, additional, Hines, Kirk, additional, Iyer, Malliga R., additional, van den Berg, Arjen, additional, Stepnowski, Sam, additional, Zmuda, Jon, additional, Gawrisch, Klaus, additional, and Glaubitz, Clemens, additional

Published
2023
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10. Exploring the interactions of irbesartan and irbesartan–2-hydroxypropyl-β-cyclodextrin complex with model membranes

Author

Liossi, Αdamantia S., Ntountaniotis, Dimitrios, Kellici, Tahsin F., Chatziathanasiadou, Maria V., Megariotis, Grigorios, Mania, Maria, Becker-Baldus, Johanna, Kriechbaum, Manfred, Krajnc, Andraž, Christodoulou, Eirini, Glaubitz, Clemens, Rappolt, Michael, Amenitsch, Heinz, Mali, Gregor, Theodorou, Doros N., Valsami, Georgia, Pitsikalis, Marinos, Iatrou, Hermis, Tzakos, Andreas G., and Mavromoustakos, Thomas

Published
2017
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23. Comparative study of the AT1 receptor prodrug antagonist candesartan cilexetil with other sartans on the interactions with membrane bilayers

Author

Fotakis, Charalambos, Megariotis, Grigorios, Christodouleas, Dionysios, Kritsi, Eftichia, Zoumpoulakis, Panagiotis, Ntountaniotis, Dimitrios, Zervou, Maria, Potamitis, Constantinos, Hodzic, Aden, Pabst, Georg, Rappolt, Michael, Mali, Gregor, Baldus, Johanna, Glaubitz, Clemens, Papadopoulos, Manthos G., Afantitis, Antreas, Melagraki, Georgia, and Mavromoustakos, Thomas

Published
2012
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25. Structural and functional consequences of the H180A mutation of the light-driven sodium pump KR2

Author

Kriebel, Clara Nassrin, Asido, Marvin, Kaur, Jagdeep, Orth, Jennifer, Braun, Philipp, Becker-Baldus, Johanna, Wachtveitl, Josef, Glaubitz, Clemens, Kriebel, Clara Nassrin, Asido, Marvin, Kaur, Jagdeep, Orth, Jennifer, Braun, Philipp, Becker-Baldus, Johanna, Wachtveitl, Josef, and Glaubitz, Clemens

Abstract

Krokinobacter eikastus rhodopsin 2 (KR2) is a light-driven pentameric sodium pump. Its ability to translocate cations other than protons and to create an electrochemical potential makes it an attractive optogenetic tool. Tailoring its ion pumping characteristics by mutations is therefore of great interest. In addition, understanding the functional and structural consequences of certain mutations helps to derive a functional mechanism of ion selectivity and transfer of KR2. Based on solid-state NMR spectroscopy, we report an extensive chemical shift resonance assignment of KR2 within lipid bilayers. This data set was then used to probe site-resolved allosteric effects of sodium binding, which revealed multiple responsive sites including the Schiff base nitrogen and the NDQ motif. Based on this data set, the consequences of the H180A mutation are probed. The mutant is silenced in the presence of sodium while in its absence, proton pumping is observed. Our data reveal specific long-range effects along the sodium transfer pathway. These experiments are complemented by time-resolved optical spectroscopy. Our data suggest a model in which sodium uptake by the mutant can still take place, while sodium release and backflow control are disturbed.

Published
2022

32. Probing the photointermediates of light-driven sodium ion pump KR2 by DNP-enhanced solid-state NMR

Author

Jakdetchai, Orawan, Eberhardt, Peter, Asido, Marvin, Kaur, Jagdeep, Kriebel, Clara Nassrin, Mao, Jiafei, Leeder, Alexander J., Brown, Lynda J., Brown, Richard C. D., Becker-Baldus, Johanna, Bamann, Christian, Wachtveitl, Josef, and Glaubitz, Clemens

Subjects
Ions, Rhodopsin, Magnetic Resonance Spectroscopy, organic chemicals, Sodium, technology, industry, and agriculture, Biophysics, SciAdv r-articles, hemic and immune systems, chemical and pharmacologic phenomena, complex mixtures, Carbon, Structural Biology, Sodium-Potassium-Exchanging ATPase, Flavobacteriaceae, Research Articles, Research Article
Abstract

Chromophore perturbations in the sodium transport intermediate states of KR2 are revealed by DNP-enhanced ssNMR., The functional mechanism of the light-driven sodium pump Krokinobacter eikastus rhodopsin 2 (KR2) raises fundamental questions since the transfer of cations must differ from the better-known principles of rhodopsin-based proton pumps. Addressing these questions must involve a better understanding of its photointermediates. Here, dynamic nuclear polarization–enhanced solid-state nuclear magnetic resonance spectroscopy on cryo-trapped photointermediates shows that the K-state with 13-cis retinal directly interconverts into the subsequent L-state with distinct retinal carbon chemical shift differences and an increased out-of-plane twist around the C14-C15 bond. The retinal converts back into an all-trans conformation in the O-intermediate, which is the key state for sodium transport. However, retinal carbon and Schiff base nitrogen chemical shifts differ from those observed in the KR2 dark state all-trans conformation, indicating a perturbation through the nearby bound sodium ion. Our findings are supplemented by optical and infrared spectroscopy and are discussed in the context of known three-dimensional structures.

Published
2021

44. Light dynamics of the retinal-disease-relevant G90D bovine rhodopsin mutant

Author

Kubatova, Nina, Mao, Jiafei, Eckert, Carl Elias, Saxena, Krishna, Gande, Santosh Lakshmi, Wachtveitl, Josef, Glaubitz, Clemens, and Schwalbe, Harald

Subjects
genetic structures, ddc:570, ddc:610
Abstract

The RHO gene encodes the G-protein-coupled receptor (GPCR) rhodopsin. Numerous mutations associated with impaired visual cycle have been reported; the G90D mutation leads to a constitutively active mutant form of rhodopsin that causes CSNB disease. We report on the structural investigation of the retinal configuration and conformation in the binding pocket in the dark and light-activated state by solution and MAS-NMR spectroscopy. We found two long-lived dark states for the G90D mutant with the 11-cis retinal bound as Schiff base in both populations. The second minor population in the dark state is attributed to a slight shift in conformation of the covalently bound 11-cis retinal caused by the mutation-induced distortion on the salt bridge formation in the binding pocket. Time-resolved UV/Vis spectroscopy was used to monitor the functional dynamics of the G90D mutant rhodopsin for all relevant time scales of the photocycle. The G90D mutant retains its conformational heterogeneity during the photocycle.

Published
2020

45. Asymmetric ATP hydrolysis cycle of the heterodimeric multidrug ABC transport complex TmrAB from Thermus thermophilus

Author

Zutz, Ariane, Hoffmann, Jan, Hellmich, Ute, Glaubitz, Clemens, Ludwig, Bernd, Brutschy, Bernd, Tampé, Robert, Zutz, Ariane, Hoffmann, Jan, Hellmich, Ute, Glaubitz, Clemens, Ludwig, Bernd, Brutschy, Bernd, and Tampé, Robert

Abstract

ATP-binding cassette (ABC) systems translocate a wide range of solutes across cellular membranes. The thermophilic Gram-negative eubacterium Thermus thermophilus, a model organism for structural genomics and systems biology, discloses ∼46 ABC proteins, which are largely uncharacterized. Here, we functionally analyzed the first two and only ABC half-transporters of the hyperthermophilic bacterium, TmrA and TmrB. The ABC system mediates uptake of the drug Hoechst 33342 in inside-out oriented vesicles that is inhibited by verapamil. TmrA and TmrB form a stable heterodimeric complex hydrolyzing ATP with a Km of 0.9 mm and kcat of 9 s−1 at 68 °C. Two nucleotides can be trapped in the heterodimeric ABC complex either by vanadate or by mutation inhibiting ATP hydrolysis. Nucleotide trapping requires permissive temperatures, at which a conformational ATP switch is possible. We further demonstrate that the canonic glutamate 523 of TmrA is essential for rapid conversion of the ATP/ATP-bound complex into its ADP/ATP state, whereas the corresponding aspartate in TmrB (Asp-500) has only a regulatory role. Notably, exchange of this single noncanonic residue into a catalytic glutamate cannot rescue the function of the E523Q/D500E complex, implicating a built-in asymmetry of the complex. However, slow ATP hydrolysis in the newly generated canonic site (D500E) strictly depends on the formation of a posthydrolysis state in the consensus site, indicating an allosteric coupling of both active sites.

Published
2021

46. The desensitized channelrhodopsin-2 photointermediate contains 13 -cis, 15 -syn retinal Schiff base

Author

Becker-Baldus, Johanna, Leeder, Alexander, Brown, Lynda J., Brown, C. D., Bamann, Christian, Glaubitz, Clemens, Becker-Baldus, Johanna, Leeder, Alexander, Brown, Lynda J., Brown, C. D., Bamann, Christian, and Glaubitz, Clemens

Abstract

Channelrhodopsin-2 (ChR2) is a light-gated cation channel and was used to lay the foundations of optogenetics. Its dark state X-ray structure has been determined in 2017 for the wild-type, which is the prototype for all other ChR variants. However, the mechanistic understanding of the channel function is still incomplete in terms of structural changes after photon absorption by the retinal chromophore and in the framework of functional models. Hence, detailed information needs to be collected on the dark state as well as on the different photointermediates. For ChR2 detailed knowledge on the chromophore configuration in the different states is still missing and a consensus has not been achieved. Using DNP-enhanced solid-state MAS NMR spectroscopy on proteoliposome samples, we unambiguously determined the chromophore configuration in the desensitized state, and we show that this state occurs towards the end of the photocycle.

Published
2021

47. [sup.15]N photochemically induced dynamic nuclear polarization magic-angle spinning NMR analysis of the electron donor of photosystem II

Author

Diller, Anna, Roy, Esha, Gast, Peter, van Gorkom, Hans J., de Groot, Huub J.M., Glaubitz, Clemens, Jeschke, Gunnar, Matysik, Jorg, and Alia, A.

Subjects
Photosystem II -- Chemical properties, Electron transport -- Evaluation, Polarization (Nuclear physics) -- Evaluation, Organic photochemistry -- Research, Oxidation-reduction reaction -- Evaluation, Science and technology
Abstract

In natural photosynthesis, the two photosystems that operate in series to drive electron transport from water to carbon dioxide are quite similar in structure and function, but operate at widely different potentials. In both systems photochemistry begins by photo-oxidation of a chlorophyll a, but that in photosystem II (PS2) has a 0.7 eV higher midpoint potential than that in photosystem I (PS1), so their electronic structures must be very different. Using reaction centers from [sup.15]N-labeled spinach, these electronic structures are compared by their photochemically induced dynamic nuclear polarization (photo-CIDNP) in magic-angle spinning (MAS) NMR measurements. The results show that the electron spin distribution in PS1, apart from its known delocalization over 2 chlorophyll molecules, reveals no marked disturbance, whereas the pattern of electron spin density distribution in PS2 is inverted in the oxidized radical state. A model for the donor of PS2 is presented explaining the inversion of electron spin density based on a tilt of the axial histidine toward pyrrole ring IV causing [pi]-[pi] overlap of both aromatic systems. photosynthesis | photosystem I | solid-state NMR | electron transfer | redox potential

Published
2007

50. Observations of light-induced structural changes of retinal within rhodopsin

Author

Grobner, Gerhard, Burnett, Ian J., Glaubitz, Clemens, Choi, Gregory, Mason, A. James, and Watts, Anthony

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Gerhard Gröbner [1]; Ian J. Burnett; Clemens Glaubitz; Gregory Choi [2]; A. James Mason; Anthony Watts (corresponding author) Photo-isomerization of the 11-cis retinal chromophore activates the mammalian light-receptor rhodopsin [...]

Published
2000
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