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Structure, regulation, interfacial enzymology, and functions of lipid metabolizing enzymes involved in signal transduction cascades
A major effort in our laboratory focuses on understanding the biochemistry and chemistry underlying the molecular aspects involved in regulating lipid metabolizing signaling enzymes and the physiological roles of this regulation. Control of lipid metabolizing enzymes involves the modulation of two key parameters; their sub-cellular distribution and their intrinsic enzymatic activity. Our studies have concentrated on three families of lipid-metabolizing signaling enzymes: diacylglycerol kinases, phospholipases D, and phospholipases C.
Interfacial Enzymology: One interest of the laboratory is the interfacial enzymology of these lipid-metabolizing enzymes: We are particularly interested in identifying the critical modulating proteins, lipids, and post-translational modifications that alter the localization and/or activity of these enzymes. In these studies, we consider the fact that as interfacial enzymes their regulation includes a number of interfacial-dependent parameters. Our recent studies have identified some of the altered interfacial parameters of the activated diacylglycerol metabolizing enzyme DGK-theta. One discovery is that activation of DGK-theta requires a cellular protein that contains a polybasic region. Some current studies center on identifying the endogenous activator in neurons.
Enzyme Structure/Function Studies: We have begun a major collaboration with Drs. Sandra Gabelli and Mario Amzel in the Department of Biophysics and Biophysical Chemistry to understand the structural dynamics of DGK-theta that governs its subcellular distribution and enzymatic activity. These studies will assist us in elucidating the catalytic mechanism(s) of this and related enzymes.
Physiological Functions of DGKs in Neurons: There is growing evidence that DGKs play physiological roles in mammalian neurons. This evidence includes cellular localization of specific isoforms, and the observations that likely modulate (a) susceptibility to epileptic seizures (DGK-epsilon), (b) neuronal spine density (DGKs beta and zeta), and (c) pre-synaptic glutamate release during DHPG (3,5-dihydroxyphenylglycine)-induced long-term potentiation (DGK-iota). In collaboration with Dr. Rich Huganier's laboratory, we showed that DGK-theta modulates synaptic vesicle cycle, and therefore glutamate release, in central nervous system neurons by modulating compensatory endocytosis. Other studies concentrate on the role of other lipid-metabolizing enzymes, such as phospholipases D, in modulating synaptic vesicle cycling
Ma Q, Gabelli SB, Raben DM (2019). Diacylglycerol kinases: Relationship to other lipid kinases. Adv. Biol. Reg. 71:104-10.
Barber C., Raben, DM (2018) Glial and Neuronal Lipid Metabolism in Neurotransmission. Frontier in Cellular Neuroscience. In Press
Barber CN, Huganir RL, Raben DM. Phosphatidic acid-producing enzymes regulating the synaptic vesicle cycle: Role for PLD? (2018) Adv. Biol. Reg. 67:141-7.
Tu-Sekine, B, Raben, DM (2017) Measuring Diacylglycerol Kinase-θ Activity and Binding. Methods Enzymol. 583:231-253.
Tu-Sekine, B, Goldschmidt, HL, Raben, DM (2017) DGK-θ: Structure, Enzymology, and Physiological Roles Frontiers in Cell and Dev. Biol. Invited Review. Published online: http://journal.frontiersin.org/article/10.3389/fcell.2016.00101/full.
Barber, C, Raben, DM (2017) Phosphatidic Acid and Neurotransmission. Adv. Biol. Reg. Jan 63:15-21.
Goldschmidt, HL, Tu-Sekine, B, Volk, L, Anggono, V, Huganir, R., and Raben, DM (2016) DGK-θ Activity is Required for Efficient Recycling of Presynaptic Vesicles at Excitatory Synapses. Cell Reports. 14(2): 200-207.
Tu-Sekine, B., Goldschmidt, H, Raben, DM (2015) Diacylglycerol, Phosphatidic Acid, and their Metabolizing Enzymes in Synaptic Vesicle Recycling. Adv. Biol. Reg. Jan;57:147-52.
Petro E, and Raben DM. (2013) Bacterial expression strategies for several Sus scrofa diacylglycerol kinase alpha constructs: solubility challenges. Scientific Reports 2013;3:160.
Ueda S, Tu-Sekine B, Yamanoue M, Raben DM, and Shirai Y. (2013) The expression of diacylglycerol kinase theta during the organogenesis of mouse embryos. BMC Developmental Biology 2013, 13:35.
Bolduc D, Rahdar M, Tu-Sekine B, Sivakumaren SC, Raben DM, Amzel LM, Devreotes P, Gabelli SB, and Cole P. (2013) Phosphorylation-mediated PTEN conformational closure and deactivation revealed with protein semisynthesis. Elife 2013 Jul 9;2:e00691.
Tu-Sekine B, Goldschmidt H, Petro E, and Raben DM. (2013) Diacylglycerol Kinase Theta: Regulation and Stability. Adv. Biol. Reg. Jan;53(1):118-26
Tu-Sekine B, and Raben DM. (2012) Dual Regulation of DGK-theta: Polybasic Proteins Promote Activation by Phospholipids and Increase Substrate Affinity. J. Biol. Chem. 287(50):41619-41627.
Tu-Sekin, B, and Raben DM. (2011) Regulation and Roles of Neuronal Diacylglycerol Kinases: a Lipid Perspective. Crit. Rev. Biochem. Mol. Biol. Oct;46(5):353-64.
Mohan S, Tse CM, Gabelli SB, Sarker R, Cha B, Fahie K, Nadella M, Zachos NC, Tu-Sekine B, Raben DM, Amzel LM, Donowitz M. (2010) NHE3 Activity Is Dependent on Direct Phosphoinositide Binding at the N Terminus of Its Intracellular Cytosolic Region. J. Biol. Chem. 285(45): 34566-78.
Tu-Sekine, B. and Raben DM. (2010) Characterization of Cellular DGK-theta. Advances in Enzyme Reg. 50:81-94.
Link TM, Park U, Vonakis BM, Raben DM, Soloski M.J., Caterina MJ. (2010) TRPV2 plays a pivotal role in macrophage particle binding and phagocytosis. Nature Immunology Mar;11(3):232-9. Epub 2010 Jan 31.
Tu-Sekine and Raben DM. (2009) Regulation of DGK-theta J. Cell Physiol. 220(3):548-52.
Raben DM and Wattenberg BW. (2009) Signaling at the Membrane Interface by the DGK/SK Enzyme Family. J Lipid Res 50th Anniversary Edition: J. Lipid Res. April Supplement: S35-S39.
Raben DM and Tu-Sekine B. (2008) Nuclear Localization Of Diacylglycerol Kinases: Regulation And Roles. Frontiers in Bioscience 13:590-597.
Wattenberg BW and Raben DM. (2007) Diacylglycerol Kinases Put the Brakes on Immune Function. Science STKE (398) pe43.
Tu-Sekine B, Ostroski M, and Raben DM. (2007) Modulation of DGK-theta Activity by alpha-Thrombin and Phospholipids. Biochemistry, 46(3): 924 -932.