Investigation of the impact of PTMs on the protein backbone conformation
Post-translational modifications (PTMs) are known to play a critical role in the regulation of protein functions. Their impact on protein structures and their link to disorder regions have already been spotted in the past decade. Nonetheless, the high diversity of PTM types and the multiple schemes of protein modifications (multiple PTMs, of different types, at different time, etc.) make difficult the direct confrontation of PTM annotations and protein structure data. Therefore, we analyzed the impact of the residue modifications on the protein structures at the local level. Thanks to a dedicated structure database, namely PTM-SD, a large screen of PTMs have been done and analyzed at local protein conformation levels using the structural alphabet protein blocks (PBs). We investigated the relation between PTMs and the backbone conformation of modified residues, of their local environment, and at the level of the complete protein structure. The two main PTM types (N-glycosylation and phosphorylation) have been studied in non-redundant datasets, and then four different proteins were focused, covering three types of PTMs: N-glycosylation in renin endopeptidase and liver carboxylesterase, phosphorylation in cyclin-dependent kinase 2 (CDK2), and methylation in actin. We observed that PTMs could either stabilize or destabilize the backbone structure, at a local and global scale, and that these effects depend on the PTM types.
KeywordsRigidity Mobility Deformability N-Glycosylation Phosphorylation Methylation Statistics Renin endopeptidase Liver carboxylesterase Cyclin-dependent kinase 2 (CDK2) Actin
This work was supported by grants from the Ministry of Research (France), University of Paris Diderot, Sorbonne Paris Cité, National Institute for Blood Transfusion (INTS, France), and Institute for Health and Medical Research (INSERM, France). PC acknowledges grant from the French Ministry of Research. Calculations were done on SGI cluster granted by Conseil Régional—Ile de France and INTS (SESAME Grant). The authors were granted access to high-performance computing (HPC) resources at the French National Computing Center CINES under Grant no. c2013037147 funded by the GENCI (Grand Equipement National de Calcul Intensif). TN and AdB acknowledge the Indo-French Centre for the Promotion of Advanced Research/CEFIPRA for collaborative Grant (Number 5302-2). This study was supported by a grant from the Laboratory of Excellence GR-Ex, reference ANR-11-LABX-0051. The labex GR-Ex is funded by the program Investissements d’avenir of the French National Research Agency, reference ANR-11-IDEX-0005-02. This work is supported by a grant from the French National Research Agency (ANR): NaturaDyRe (ANR-2010-CD2I-014-04) to JR and AdB.
The funding bodies have no role in the design of the study and collection, analysis, interpretation of data, and in writing the manuscript.
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Conflict of interest
The authors declare no conflict of interest.
All authors have been personally and actively involved in substantive work leading to the manuscript and will hold themselves jointly and individually for its contents. This material has not been published in whole or in part elsewhere. The manuscript is not currently being considered for publication in another journal.
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