The Experts below are selected from a list of 138444 Experts worldwide ranked by ideXlab platform
William Dowhan - One of the best experts on this subject based on the ideXlab platform.
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molecular genetic approaches to defining Lipid Function
Journal of Lipid Research, 2009Co-Authors: William DowhanAbstract:Lipids fulfill multiple and diverse Functions in cells. Establishing the molecular basis for these Functions has been challenging due to the lack of catalytic activity of Lipids and the pleiotropic effects of mutations that affect Lipid composition. By combining molecular genetic manipulation of membrane Lipid composition with biochemical characterization of the resulting phenotypes, the molecular details of novel Lipid Functions have been established. This review summarizes the results of such a combined approach to defining Lipid Function in bacteria.
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Lipids in the assembly of membrane proteins and organization of protein supercomplexes implications for Lipid linked disorders
Sub-cellular biochemistry, 2008Co-Authors: Mikhail V Bogdanov, Eugenia Mileykovskaya, William DowhanAbstract:Lipids play important roles in cellular dysFunction leading to disease. Although a major role for phosphoLipids is in defining the membrane permeability barrier, phosphoLipids play a central role in a diverse range of cellular processes and therefore are important factors in cellular dysFunction and disease. This review is focused on the role of phosphoLipids in normal assembly and organization of the membrane proteins, multimeric protein complexes, and higher order supercomplexes. Since Lipids have no catalytic activity, it is difficult to determine their Function at the molecular level. Lipid Function has generally been defined by affects on protein Function or cellular processes. Molecular details derived from genetic, biochemical, and structural approaches are presented for involvement of phosphatidylethanolamine and cardiolipin in protein organization. Experimental evidence is presented that changes in phosphatidylethanolamine levels results in misfolding and topological misorientation of membrane proteins leading to dysFunctional proteins. Examples are presented for diseases in which proper protein folding or topological organization is not attained due to either demonstrated or proposed involvement of a Lipid. Similar changes in cardiolipin levels affects the structure and Function of individual components of the mitochondrial electron transport chain and their organization into supercomplexes resulting in reduced mitochondrial oxidative phosphorylation efficiency and apoptosis. Diseases in which mitochondrial dysFunction has been linked to reduced cardiolipin levels are described. Therefore, understanding the principles governing Lipid-dependent assembly and organization of membrane proteins and protein complexes will be useful in developing novel therapeutic approaches for disorders in which Lipids play an important role.
Kenjiro Yoshimura - One of the best experts on this subject based on the ideXlab platform.
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Lipid protein interaction of the mscs mechanosensitive channel examined by scanning mutagenesis
Biophysical Journal, 2006Co-Authors: Takeshi Nomura, Masahiro Sokabe, Kenjiro YoshimuraAbstract:The mechanosensitive channel of small conductance (MscS) is a bacterial mechanosensitive channel that opens in response to rapid hypoosmotic stress. Since MscS can be opened solely by membrane stretch without help from any accessory protein, the Lipid-protein interface must play a crucial role in sensing membrane tension. In this study, the hydrophobic residues in the Lipid-protein interface were substituted one by one with a hydrophilic amino acid, asparagine, to modify the interaction between the protein and the Lipid. Function of the mutant MscSs was examined by patch-clamp and hypoosmotic shock experiments. An increase in the gating threshold and a decrease in the viability on hypoosmotic shock were observed when the hydrophobic residues near either end of the first or the second transmembrane helix (TM1 or TM2) were replaced with asparagine. This observation indicates that the Lipid-protein interaction at the ends of both helices (TM1 and TM2) is essential to MscS Function.
Heidi E Bostic - One of the best experts on this subject based on the ideXlab platform.
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exploiting bioorthogonal chemistry to elucidate protein Lipid binding interactions and other biological roles of phosphoLipids
Accounts of Chemical Research, 2011Co-Authors: Michael D Best, Meng M Rowland, Heidi E BosticAbstract:Lipids play critical roles in a litany of physiological and pathophysiological events, often through the regulation of protein Function. These activities are generally difficult to characterize, however, because the membrane environment in which Lipids operate is very complex. Moreover, Lipids have a diverse range of biological Functions, including the recruitment of proteins to membrane surfaces, actions as small-molecule ligands, and covalent protein modification through Lipidation. Advancements in the development of bioorthogonal reactions have facilitated the study of Lipid activities by providing the ability to selectively label probes bearing bioorthogonal tags within complex biological samples.In this Account, we discuss recent efforts to harness the beneficial properties of bioorthogonal labeling strategies in elucidating Lipid Function. Initially, we summarize strategies for the design and synthesis of Lipid probes bearing bioorthogonal tags. This discussion includes issues to be considered when ...
Giulio Supertifurga - One of the best experts on this subject based on the ideXlab platform.
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a conserved circular network of coregulated Lipids modulates innate immune responses
Cell, 2015Co-Authors: Marielle S Koberlin, Berend Snijder, Leonhard X Heinz, Christoph Baumann, Astrid Fauster, Gregory I Vladimer, Anneclaude Gavin, Giulio SupertifurgaAbstract:Lipid composition affects the biophysical properties of membranes that provide a platform for receptor-mediated cellular signaling. To study the regulatory role of membrane Lipid composition, we combined genetic perturbations of sphingoLipid metabolism with the quantification of diverse steps in Toll-like receptor (TLR) signaling and mass spectrometry-based Lipidomics. Membrane Lipid composition was broadly affected by these perturbations, revealing a circular network of coregulated sphingoLipids and glycerophosphoLipids. This evolutionarily conserved network architecture simultaneously reflected membrane Lipid metabolism, subcellular localization, and adaptation mechanisms. Integration of the diverse TLR-induced inflammatory phenotypes with changes in Lipid abundance assigned distinct Functional roles to individual Lipid species organized across the network. This Functional annotation accurately predicted the inflammatory response of cells derived from patients suffering from Lipid storage disorders, based solely on their altered membrane Lipid composition. The analytical strategy described here empowers the understanding of higher-level organization of membrane Lipid Function in diverse biological systems.
Andrej Shevchenko - One of the best experts on this subject based on the ideXlab platform.
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live cell Lipid biochemistry reveals a role of diacylglycerol side chain composition for cellular Lipid dynamics and protein affinities
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Milena Schuhmacher, Andreas T Grasskamp, Pavel Barahtjan, Nicolai Wagner, Benoit Lombardot, Jan S Schuhmacher, Pia Sala, Annett Lohmann, Ian Henry, Andrej ShevchenkoAbstract:Every cell produces thousands of distinct Lipid species, but insight into how Lipid chemical diversity contributes to biological signaling is lacking, particularly because of a scarcity of methods for quantitatively studying Lipid Function in living cells. Using the example of diacylglycerols, prominent second messengers, we here investigate whether Lipid chemical diversity can provide a basis for cellular signal specification. We generated photo-caged Lipid probes, which allow acute manipulation of distinct diacylglycerol species in the plasma membrane. Combining uncaging experiments with mathematical modeling, we were able to determine binding constants for diacylglycerol–protein interactions, and kinetic parameters for diacylglycerol transbilayer movement and turnover in quantitative live-cell experiments. Strikingly, we find that affinities and kinetics vary by orders of magnitude due to diacylglycerol side-chain composition. These differences are sufficient to explain differential recruitment of diacylglycerol binding proteins and, thus, differing downstream phosphorylation patterns. Our approach represents a generally applicable method for elucidating the biological Function of single Lipid species on subcellular scales in quantitative live-cell experiments.