Post-translational modifications of proteins in cardiovascular diseases examined by proteomic approaches.
Over 400 different types of post-translational modifications (PTMs) have been reported and over 200 various types of PTMs have been discovered using mass spectrometry (MS)-based proteomics. MS-based proteomics has proven to be a powerful method capable of global PTM mapping with the identification of modified proteins/peptides, the localization of PTM sites and PTM quantitation. PTMs play regulatory roles in protein functions, activities and interactions in various heart related diseases, such as ischemia/reperfusion injury, cardiomyopathy and heart failure. The recognition of PTMs that are specific to cardiovascular pathology and the clarification of the mechanisms underlying these PTMs at molecular levels are crucial for discovery of novel biomarkers and application in a clinical setting. With sensitive MS instrumentation and novel biostatistical methods for precise processing of the data, low-abundance PTMs can be successfully detected and the beneficial or unfavorable effects of specific PTMs on cardiac function can be determined. Moreover, computational proteomic strategies that can predict PTM sites based on MS data have gained an increasing interest and can contribute to characterization of PTM profiles in cardiovascular disorders. More recently, machine learning- and deep learning-based methods have been employed to predict the locations of PTMs and explore PTM crosstalk. In this review article, the types of PTMs are briefly overviewed, approaches for PTM identification/quantitation in MS-based proteomics are discussed and recently published proteomic studies on PTMs associated with cardiovascular diseases are included.
Stastna M
《-》
Trypanosoma cruzi cell cycle progression exhibits minimal variation in histone PTMs with unique histone H4 acetylation pattern.
Histones are crucial proteins in eukaryotic cells that undergo extensive posttranslational modifications (PTMs) such as methylation, acetylation, and phosphorylation, which are associated to chromatin structure, gene expression, DNA damage/repair and cell cycle. In Trypanosoma cruzi, the primary sequence of histones differs from that of other eukaryotes. Despite this, they display a vast range of PTMs, though their modulation throughout the cell cycle remains largely unexplored. In this study, we investigated the dynamic modulation of histone PTMs across G1/S, S, and G2/M phases of T. cruzi cell cycle using hydroxyurea- synchronized parasites. We applied a workflow that included histone derivatization, trypsin digestion followed by a high-resolution mass spectrometry and data independent analysis. Quantitative analysis of 141 histone peptide isoforms revealed that there are only minor variations in histone PTM levels throughout the cell cycle. The H3K76 trimethylation remained predominant throughout all phases, with an increase in monomethylation during G2/M. Additionally, hyperacetylation of the N-terminal region of histone H4 was observed, particularly at lysine residues 2, 5, and 10, suggesting their importance in cell cycle progression. Striking, acetylation of histone H4 at K2 and K5 increases during the S-phase, mirroring the H4K5acK12ac pattern observed in mammals, which are related to histone nuclear import and chromatin deposition. Overall, the results suggest that the T. cruzi cell cycle maintains stable global levels of histone PTMs, relying on variations in only a few specific PTMs. Further investigations are warranted to elucidate the functional significance of these PTMs and their impact on cell cycle regulation and chromatin dynamics in T. cruzi. SIGNIFICANCE: Histone posttranslational modifications (PTMs) are key regulators of chromatin architecture and cellular processes such as gene expression and cell cycle control. In Trypanosoma cruzi, the etiological agent of Chagas disease, histones have a distinct primary structure compared to other eukaryotes, yet they display a wide variety of PTMs. This study provides a comprehensive analysis of histone PTM dynamics across the G1/S, S, and G2/M phases of the T. cruzi cell cycle, revealing that global histone PTM levels remain largely stable, with variations in a few specific marks. Notably, the study highlights the increased acetylation of histone H4 at lysines 2 and 5 during the S-phase, contrasting with the well-conserved acetylation at lysines 5 and 12 observed in mammals involved in nuclear import and chromatin assembly. These findings underscore the evolutionary divergence and functional specificity of histone modifications and provide a foundation for further investigations into their roles in parasite biology, with potential implications for understanding chromatin dynamics and identifying novel therapeutic targets.
Menezes APJ
，Silber AM
，Elias MC
，da Cunha JPC
... -
《-》
Post-Translational Modifications of G Protein-Coupled Receptors Control Cellular Signaling Dynamics in Space and Time.
G protein-coupled receptors (GPCRs) are a large family comprising >800 signaling receptors that regulate numerous cellular and physiologic responses. GPCRs have been implicated in numerous diseases and represent the largest class of drug targets. Although advances in GPCR structure and pharmacology have improved drug discovery, the regulation of GPCR function by diverse post-translational modifications (PTMs) has received minimal attention. Over 200 PTMs are known to exist in mammalian cells, yet only a few have been reported for GPCRs. Early studies revealed phosphorylation as a major regulator of GPCR signaling, whereas later reports implicated a function for ubiquitination, glycosylation, and palmitoylation in GPCR biology. Although our knowledge of GPCR phosphorylation is extensive, our knowledge of the modifying enzymes, regulation, and function of other GPCR PTMs is limited. In this review we provide a comprehensive overview of GPCR post-translational modifications with a greater focus on new discoveries. We discuss the subcellular location and regulatory mechanisms that control post-translational modifications of GPCRs. The functional implications of newly discovered GPCR PTMs on receptor folding, biosynthesis, endocytic trafficking, dimerization, compartmentalized signaling, and biased signaling are also provided. Methods to detect and study GPCR PTMs as well as PTM crosstalk are further highlighted. Finally, we conclude with a discussion of the implications of GPCR PTMs in human disease and their importance for drug discovery. SIGNIFICANCE STATEMENT: Post-translational modification of G protein-coupled receptors (GPCRs) controls all aspects of receptor function; however, the detection and study of diverse types of GPCR modifications are limited. A thorough understanding of the role and mechanisms by which diverse post-translational modifications regulate GPCR signaling and trafficking is essential for understanding dysregulated mechanisms in disease and for improving and refining drug development for GPCRs.
Patwardhan A
，Cheng N
，Trejo J
《-》
ResearchGate
(全网免费下载)
钛学术
(全网免费下载)
