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|a Bhat, Vadiraja B.
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|a Massachusetts Institute of Technology. Department of Biological Engineering
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|a Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
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|a Massachusetts Institute of Technology. Department of Chemistry
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|a Picower Institute for Learning and Memory
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|a Seneviratne, Uthpala Indrajith
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|a Nott, Alexander
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|a Kodihalli, Ravindra
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|a Wishnok, John S
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|a Tsai, Li-Huei
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|a Tannenbaum, Steven R
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|a Seneviratne, Uthpala Indrajith
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|a Nott, Alexander
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|a Kodihalli, Ravindra
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|a Wishnok, John S
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|a Tsai, Li-Huei
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|a Tannenbaum, Steven R
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|a S-nitrosation of proteins relevant to Alzheimer's disease during early stages of neurodegeneration
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|b National Academy of Sciences (U.S.),
|c 2017-05-24T20:03:16Z.
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|z Get fulltext
|u http://hdl.handle.net/1721.1/109331
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|a Protein S-nitrosation (SNO-protein), the nitric oxide-mediated posttranslational modification of cysteine thiols, is an important regulatory mechanism of protein function in both physiological and pathological pathways. A key first step toward elucidating the mechanism by which S-nitrosation modulates a protein's function is identification of the targeted cysteine residues. Here, we present a strategy for the simultaneous identification of SNO-cysteine sites and their cognate proteins to profile the brain of the CK-p25-inducible mouse model of Alzheimer's disease-like neurodegeneration. The approach-SNOTRAP (SNO trapping by triaryl phosphine)-is a direct tagging strategy that uses phosphine-based chemical probes, allowing enrichment of SNO-peptides and their identification by liquid chromatography tandem mass spectrometry. SNOTRAP identified 313 endogenous SNO-sites in 251 proteins in the mouse brain, of which 135 SNO-proteins were detected only during neurodegeneration. S-nitrosation in the brain shows regional differences and becomes elevated during early stages of neurodegeneration in the CK-p25 mouse. The SNO-proteome during early neurodegeneration identified increased S-nitrosation of proteins important for synapse function, metabolism, and Alzheimer's disease pathology. In the latter case, proteins related to amyloid precursor protein processing and secretion are S-nitrosated, correlating with increased amyloid formation. Sequence analysis of SNO-cysteine sites identified potential linear motifs that are altered under pathological conditions. Collectively, SNOTRAP is a direct tagging tool for global elucidation of the SNO-proteome, providing functional insights of endogenous SNO proteins in the brain and its dysregulation during neurodegeneration.
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|a National Institutes of Health (U.S.) (NIH Grant CA26731)
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|a Massachusetts Institute of Technology. Center for Environmental Health Sciences (Grant ES002109)
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|a Simons Foundation
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|a National Institutes of Health (U.S.) (NIH Grant R01 NS051874)
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|a en_US
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|a Article
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|t Proceedings of the National Academy of Sciences of the United States of America
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