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bioRxiv · 10.1101/2023.05.26.542474

Integrated Analysis of Cross-Links and Deadend Peptides for Enhanced Interpretation ofQuantitative XL-MS

Keller, A.·Tang, X.·Bruce, J. E.
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Abstract

XL-MS provides low-resolution structural information of proteins in cells and tissues. Combined with quantitation, it can identify changes in the interactome between samples, for example, control and drug-treated cells, or young and old mice. A difference can originate from protein conformational changes altering the solvent-accessible distance separating the cross-linked residues. Alternatively, a difference can result from conformational changes localized to the cross-linked residues, for example, altering the solvent exposure or reactivity of those residues or post-translational modifications on the cross-linked peptides. In this manner, cross-linking is sensitive to a variety of protein conformational features. Dead-end peptides are cross-links attached only at one end to a protein, the other terminus being hydrolyzed. As a result, changes in their abundance reflect only conformational changes localized to the attached residue. For this reason, analyzing both quantified cross-links and their corresponding dead-end peptides can help elucidate the likely conformational changes giving rise to observed differences of cross-link abundance. We describe analysis of dead-end peptides in the XLinkDB public cross-link database and, with quantified mitochondrial data isolated from failing heart versus healthy mice, show how a comparison of abundance ratios between cross-links and their corresponding dead-end peptides can be leveraged to reveal possible conformational explanations.

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Keller, A., Tang, X., Bruce, J. E.. 2023-05-29. Integrated Analysis of Cross-Links and Deadend Peptides for Enhanced Interpretation ofQuantitative XL-MS. https://doi.org/10.1101/2023.05.26.542474

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