TY - JOUR

T1 - The structural context of posttranslational modifications at a proteome-wide scale

AU - Bludau, Isabell

AU - Willems, Sander

AU - Zeng, Wen Feng

AU - Strauss, Maximilian T.

AU - Hansen, Fynn M.

AU - Tanzer, Maria C.

AU - Karayel, Ozge

AU - Schulman, Brenda A.

AU - Mann, Matthias

N1 - Publisher Copyright: © 2022 Bludau et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2022

Y1 - 2022

N2 - AThUe:rPecleeanstecreovnofilrumtitohnatianllchoemadpinugtaletvioenlsaalrperroepteriensesntrteudcctuorrerepctrleyd: iction provides folding models for entire proteomes, which can now be integrated with large-scale experimental data. Mass spectrometry (MS)-based proteomics has identified and quantified tens of thousands of posttranslational modifications (PTMs), most of them of uncertain functional relevance. In this study, we determine the structural context of these PTMs and investigate how this information can be leveraged to pinpoint potential regulatory sites. Our analysis uncovers global patterns of PTM occurrence across folded and intrinsically disordered regions. We found that this information can help to distinguish regulatory PTMs from those marking improperly folded proteins. Interestingly, the human proteome contains thousands of proteins that have large folded domains linked by short, disordered regions that are strongly enriched in regulatory phosphosites. These include well-known kinase activation loops that induce protein conformational changes upon phosphorylation. This regulatory mechanism appears to be widespread in kinases but also occurs in other protein families such as solute carriers. It is not limited to phosphorylation but includes ubiquitination and acetylation sites as well. Furthermore, we performed three-dimensional proximity analysis, which revealed examples of spatial coregulation of different PTM types and potential PTM crosstalk. To enable the community to build upon these first analyses, we provide tools for 3D visualization of proteomics data and PTMs as well as python libraries for data accession and processing.

AB - AThUe:rPecleeanstecreovnofilrumtitohnatianllchoemadpinugtaletvioenlsaalrperroepteriensesntrteudcctuorrerepctrleyd: iction provides folding models for entire proteomes, which can now be integrated with large-scale experimental data. Mass spectrometry (MS)-based proteomics has identified and quantified tens of thousands of posttranslational modifications (PTMs), most of them of uncertain functional relevance. In this study, we determine the structural context of these PTMs and investigate how this information can be leveraged to pinpoint potential regulatory sites. Our analysis uncovers global patterns of PTM occurrence across folded and intrinsically disordered regions. We found that this information can help to distinguish regulatory PTMs from those marking improperly folded proteins. Interestingly, the human proteome contains thousands of proteins that have large folded domains linked by short, disordered regions that are strongly enriched in regulatory phosphosites. These include well-known kinase activation loops that induce protein conformational changes upon phosphorylation. This regulatory mechanism appears to be widespread in kinases but also occurs in other protein families such as solute carriers. It is not limited to phosphorylation but includes ubiquitination and acetylation sites as well. Furthermore, we performed three-dimensional proximity analysis, which revealed examples of spatial coregulation of different PTM types and potential PTM crosstalk. To enable the community to build upon these first analyses, we provide tools for 3D visualization of proteomics data and PTMs as well as python libraries for data accession and processing.

U2 - 10.1371/journal.pbio.3001636

DO - 10.1371/journal.pbio.3001636

M3 - Journal article

C2 - 35576205

AN - SCOPUS:85130410312

VL - 20

JO - PLoS Biology

JF - PLoS Biology

SN - 1544-9173

IS - 5

M1 - e3001636

ER -