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Covalent Protein Painting Reveals Structural Changes in the Proteome in Alzheimer Disease

View ORCID ProfileTom Casimir Bamberger, View ORCID ProfileSandra Pankow, View ORCID ProfileSalvador Martínez-Bartolomé, View ORCID ProfileMichelle Ma, Jolene K Diedrich, View ORCID ProfileRobert A Rissman, View ORCID ProfileJohn Robert Yates III
doi: https://doi.org/10.1101/2020.01.31.929117
Tom Casimir Bamberger
Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.;
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  • For correspondence: cbamberg@scripps.edu
Sandra Pankow
Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.;
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  • For correspondence: pankows@scripps.edu
Salvador Martínez-Bartolomé
Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.;
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  • For correspondence: salvador@scripps.edu
Michelle Ma
Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.;
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  • For correspondence: michellema@fas.harvard.edu
Jolene K Diedrich
Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.;
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  • For correspondence: jdiedric@scripps.edu
Robert A Rissman
Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA., and Veterans Affairs San Diego Healthcare System, San Diego, CA, 92161, USA.
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John Robert Yates
Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.;
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  • For correspondence: jyates@scripps.edu
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Abstract

The 3D structures of aberrant protein folds have been visualized in exquisite detail, yet no method has been able to quantitatively measure protein misfolding across a proteome. Here, we present Covalent Protein Painting (CPP), a mass spectrometry-based structural proteomics approach to quantify the accessibility of lysine ϵ-amines for chemical modification at the surface of natively folded proteins. We used CPP to survey 2,645 lysine residues in the proteome of HEK293T cells in vivo and found that mild heat shock increased rather than decreased lysine accessibility for chemical modification. CPP was able to differentiate patients with Alzheimer disease (AD) or Lewy body disease (LBD) or both from controls based on relative accessibility of lysine residues K147, K137, and K28 in Tubulin-β, Succinate dehydrogenase, and amyloid-β peptide, respectively. The alterations of Tubulin-β and Succinate dehydrogenase hint to broader perturbations of the proteome in AD beyond amyloid-β and hyper-phosphorylated tau.

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Posted February 02, 2020.
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Covalent Protein Painting Reveals Structural Changes in the Proteome in Alzheimer Disease
Tom Casimir Bamberger, Sandra Pankow, Salvador Martínez-Bartolomé, Michelle Ma, Jolene K Diedrich, Robert A Rissman, John Robert Yates III
bioRxiv 2020.01.31.929117; doi: https://doi.org/10.1101/2020.01.31.929117
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Covalent Protein Painting Reveals Structural Changes in the Proteome in Alzheimer Disease
Tom Casimir Bamberger, Sandra Pankow, Salvador Martínez-Bartolomé, Michelle Ma, Jolene K Diedrich, Robert A Rissman, John Robert Yates III
bioRxiv 2020.01.31.929117; doi: https://doi.org/10.1101/2020.01.31.929117

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