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Identification of Cofragmented Combinatorial Peptide Isomers by Two-Dimensional Partial Covariance Mass Spectrometry

[Image: see text] Combinatorial post-translational modifications (PTMs), such as those forming the so-called “histone code”, have been linked to cell differentiation, embryonic development, cellular reprogramming, aging, cancers, neurodegenerative disorders, etc. Nevertheless, a reliable mass spectr...

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Autores principales: Driver, Taran, Pipkorn, Rüdiger, Averbukh, Vitali, Frasinski, Leszek J., Marangos, Jon P., Edelson-Averbukh, Marina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10326914/
https://www.ncbi.nlm.nih.gov/pubmed/37252811
http://dx.doi.org/10.1021/jasms.3c00111
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author Driver, Taran
Pipkorn, Rüdiger
Averbukh, Vitali
Frasinski, Leszek J.
Marangos, Jon P.
Edelson-Averbukh, Marina
author_facet Driver, Taran
Pipkorn, Rüdiger
Averbukh, Vitali
Frasinski, Leszek J.
Marangos, Jon P.
Edelson-Averbukh, Marina
author_sort Driver, Taran
collection PubMed
description [Image: see text] Combinatorial post-translational modifications (PTMs), such as those forming the so-called “histone code”, have been linked to cell differentiation, embryonic development, cellular reprogramming, aging, cancers, neurodegenerative disorders, etc. Nevertheless, a reliable mass spectral analysis of the combinatorial isomers represents a considerable challenge. The difficulty stems from the incompleteness of information that could be generated by the standard MS to differentiate cofragmented isomeric sequences in their naturally occurring mixtures based on the fragment mass-to-charge ratio and relative abundance information only. Here we show that fragment–fragment correlations revealed by two-dimensional partial covariance mass spectrometry (2D-PC-MS) allow one to solve the combinatorial PTM puzzles that cannot be tackled by the standard MS as a matter of principle. We introduce 2D-PC-MS marker ion correlation approach and demonstrate experimentally that it can provide the missing information enabling identification of cofragmentated combinatorially modified isomers. Our in silico study shows that the marker ion correlations can be used to unambiguously identify 5 times more cofragmented combinatorially acetylated tryptic peptides and 3 times more combinatorially modified Glu-C peptides of human histones than is possible using standard MS methods.
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spelling pubmed-103269142023-07-08 Identification of Cofragmented Combinatorial Peptide Isomers by Two-Dimensional Partial Covariance Mass Spectrometry Driver, Taran Pipkorn, Rüdiger Averbukh, Vitali Frasinski, Leszek J. Marangos, Jon P. Edelson-Averbukh, Marina J Am Soc Mass Spectrom [Image: see text] Combinatorial post-translational modifications (PTMs), such as those forming the so-called “histone code”, have been linked to cell differentiation, embryonic development, cellular reprogramming, aging, cancers, neurodegenerative disorders, etc. Nevertheless, a reliable mass spectral analysis of the combinatorial isomers represents a considerable challenge. The difficulty stems from the incompleteness of information that could be generated by the standard MS to differentiate cofragmented isomeric sequences in their naturally occurring mixtures based on the fragment mass-to-charge ratio and relative abundance information only. Here we show that fragment–fragment correlations revealed by two-dimensional partial covariance mass spectrometry (2D-PC-MS) allow one to solve the combinatorial PTM puzzles that cannot be tackled by the standard MS as a matter of principle. We introduce 2D-PC-MS marker ion correlation approach and demonstrate experimentally that it can provide the missing information enabling identification of cofragmentated combinatorially modified isomers. Our in silico study shows that the marker ion correlations can be used to unambiguously identify 5 times more cofragmented combinatorially acetylated tryptic peptides and 3 times more combinatorially modified Glu-C peptides of human histones than is possible using standard MS methods. American Chemical Society 2023-05-30 /pmc/articles/PMC10326914/ /pubmed/37252811 http://dx.doi.org/10.1021/jasms.3c00111 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Driver, Taran
Pipkorn, Rüdiger
Averbukh, Vitali
Frasinski, Leszek J.
Marangos, Jon P.
Edelson-Averbukh, Marina
Identification of Cofragmented Combinatorial Peptide Isomers by Two-Dimensional Partial Covariance Mass Spectrometry
title Identification of Cofragmented Combinatorial Peptide Isomers by Two-Dimensional Partial Covariance Mass Spectrometry
title_full Identification of Cofragmented Combinatorial Peptide Isomers by Two-Dimensional Partial Covariance Mass Spectrometry
title_fullStr Identification of Cofragmented Combinatorial Peptide Isomers by Two-Dimensional Partial Covariance Mass Spectrometry
title_full_unstemmed Identification of Cofragmented Combinatorial Peptide Isomers by Two-Dimensional Partial Covariance Mass Spectrometry
title_short Identification of Cofragmented Combinatorial Peptide Isomers by Two-Dimensional Partial Covariance Mass Spectrometry
title_sort identification of cofragmented combinatorial peptide isomers by two-dimensional partial covariance mass spectrometry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10326914/
https://www.ncbi.nlm.nih.gov/pubmed/37252811
http://dx.doi.org/10.1021/jasms.3c00111
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