S-nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration
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 modulat...
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2017
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| Online Access: | http://hdl.handle.net/1721.1/109331 https://orcid.org/0000-0001-6774-9639 https://orcid.org/0000-0002-2029-7193 https://orcid.org/0000-0002-2325-552X https://orcid.org/0000-0003-1262-0592 |
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| author | Bhat, Vadiraja B. Seneviratne, Uthpala Indrajith Nott, Alexander Kodihalli, Ravindra Wishnok, John S Tsai, Li-Huei Tannenbaum, Steven R |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Bhat, Vadiraja B. Seneviratne, Uthpala Indrajith Nott, Alexander Kodihalli, Ravindra Wishnok, John S Tsai, Li-Huei Tannenbaum, Steven R |
| author_sort | Bhat, Vadiraja B. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T15:36:18Z |
| format | Article |
| id | mit-1721.1/109331 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:36:18Z |
| publishDate | 2017 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/1093312022-09-29T15:01:12Z S-nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration Bhat, Vadiraja B. Seneviratne, Uthpala Indrajith Nott, Alexander Kodihalli, Ravindra Wishnok, John S Tsai, Li-Huei Tannenbaum, Steven R Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Massachusetts Institute of Technology. Department of Chemistry Picower Institute for Learning and Memory Seneviratne, Uthpala Indrajith Nott, Alexander Kodihalli, Ravindra Wishnok, John S Tsai, Li-Huei Tannenbaum, Steven R 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. National Institutes of Health (U.S.) (NIH Grant CA26731) Massachusetts Institute of Technology. Center for Environmental Health Sciences (Grant ES002109) Simons Foundation National Institutes of Health (U.S.) (NIH Grant R01 NS051874) 2017-05-24T20:03:16Z 2017-05-24T20:03:16Z 2016-04 2015-10 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/109331 Seneviratne, Uthpala, Alexi Nott, Vadiraja B. Bhat, Kodihalli C. Ravindra, John S. Wishnok, Li-Huei Tsai, and Steven R. Tannenbaum. “ S-Nitrosation of Proteins Relevant to Alzheimer’s Disease During Early Stages of Neurodegeneration .” Proceedings of the National Academy of Sciences 113, no. 15 (March 24, 2016): 4152–4157. https://orcid.org/0000-0001-6774-9639 https://orcid.org/0000-0002-2029-7193 https://orcid.org/0000-0002-2325-552X https://orcid.org/0000-0003-1262-0592 en_US http://dx.doi.org/10.1073/pnas.1521318113 Proceedings of the National Academy of Sciences of the United States of America Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | Bhat, Vadiraja B. Seneviratne, Uthpala Indrajith Nott, Alexander Kodihalli, Ravindra Wishnok, John S Tsai, Li-Huei Tannenbaum, Steven R S-nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration |
| title | S-nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration |
| title_full | S-nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration |
| title_fullStr | S-nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration |
| title_full_unstemmed | S-nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration |
| title_short | S-nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration |
| title_sort | s nitrosation of proteins relevant to alzheimer s disease during early stages of neurodegeneration |
| url | http://hdl.handle.net/1721.1/109331 https://orcid.org/0000-0001-6774-9639 https://orcid.org/0000-0002-2029-7193 https://orcid.org/0000-0002-2325-552X https://orcid.org/0000-0003-1262-0592 |
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