Search Results (599)

Tau protein, a neuron-enriched microtubule-associated protein encoded by the MAPT gene, plays pivotal roles in microtubule stabilisation, axonal transport, and synaptic plasticity. Aberrant post-translational modifications (PTMs), hyperphosphorylation, acetylation, ubiquitination, oxidative stress and neuroinflammation disrupt tau’s normal functions, drive its mislocalization, and promote aggregation into neurofibrillary tangles, a hallmark of Alzheimer’s disease (AD) and related tauopathies. Over the past two decades, tau-targeted therapies have advanced into clinical development, yet most have failed to demonstrate efficacy in human trials. This review synthesises mechanistic insights into tau biology and pathology, highlighting phosphorylation and acetylation pathways, aggregation-prone motifs, and immune-mediated propagation. We analyse the current therapeutic landscape, including kinase and phosphatase modulators, O-GlcNAcase inhibitors, aggregation blockers, immunotherapies, and microtubule-stabilising agents, while examining representative clinical programs and the reasons underlying their limited success. By combining mechanistic understanding with clinical experience, this review outlines emerging opportunities for rational treatment development, aiming to inform future tau-targeted strategies for AD and other tauopathies. Full article

Background/Objectives: Intrinsically disordered protein regions (IDRs) are difficult to study due to their flexible nature and transient interactions. Computational folding using AlphaFold may offer one way to explore potential folding of these regions under various conditions. Human DNA topoisomerase IIα (TOP2A) is an essential enzyme involved in regulating DNA topology during replication and cell division. TOP2A has an IDR at the C-terminal domain (CTD) that has been shown to be important for regulating TOP2A function, but little is known about potential conformations that it may undertake. Methods: Utilizing the AlphaFold 3 (AF3) model by way of AlphaFold Server, TOP2A was folded as a dimer first without and then with 29 literature-supported post-translational modifications (PTMs) and DNA to observe whether there is predicted folding. Results: TOP2A CTD does not fold in the absence of PTMs. With the addition of PTMs, however, the CTD is predicted to fold into a globular bundle of loops and α-helices. While DNA alone did not induce folding, in the presence of PTMs, DNA ligands increased helicity of the folded CTD and caused it to interact at different core domain interfaces. In addition, DNA is predicted to enable folding of the TOP2A CTD in the presence of fewer PTMs when compared to the absence of DNA. Conclusions: AF3 predicts the folding of TOP2A CTD in the presence of specific PTMs, and this folding appears to shift to allow binding to DNA in functionally relevant regions. These studies provide predicted folding patterns that can be tested by biochemical approaches. AF3 may support the development of testable hypotheses regarding IDRs and enables researchers to model protein-DNA interactions. Full article

Liquid–liquid phase separation (LLPS) is a fundamental biophysical process in which proteins and nucleic acids dynamically demix from the cellular milieu to form membraneless organelles (MLO) with liquid-like properties. Environmental cues, such as light, temperature fluctuations, and pathogen interactions, induce LLPS of fungal proteins with intrinsically disordered regions (IDRs) or multimerization domains, thereby regulating fungal hyphal growth, sexual reproduction, pathogenesis, and adaptation. Recently, LLPS has emerged as a powerful tool for biomolecular research, innovative biotechnological application, biosynthesis and metabolic engineering. This review focuses on the current advances in environmental cue-triggered fungal condensates assembled by LLPS, with a focus on their roles in regulating the fungal physical biology and cellular processes including transcription, RNA modification, translation, posttranslational modification process (PTM), transport, and stress response. It further discusses the strategies of engineering synthetic biomolecular condensates in microbial cell factories to enhance production and metabolic efficiency. Full article

The ultimate function of a protein is a summation of the activities of all its modules or domains. A major mechanism for regulating protein activity, besides modulation of its levels through translation or degradation, is covalent post-translational modification (PTM) of these modules, including phosphorylation and dephosphorylation of tyrosine, threonine, and/or serine residues. Phosphorylation is a fast, reversible, and highly specific mode of regulating protein function. Unlike proteins that are marked with other PTMs, phosphorylated proteins orchestrate an extensive network of protein interactions because of their ability to bind many protein partners. Protein phosphorylation is crucial for many cellular processes—signaling, transcription, and metabolism—because it precisely controls these processes in time and space. In this review, we will focus on signaling coordinated by tyrosine phosphorylation–dephosphorylation, specifically structural insights that govern the mechanism of recognition of phosphotyrosine (pY)-containing ligands by Src homology 2 (SH2) domains. We update the approaches used to target the SH2 domains and techniques applied in drug discovery, highlighting inhibitors that have reached clinical development. Full article

Background/Objective: Aberrant acetylation and methylation of histone and non-histone proteins contribute to carcinogenesis. Among non-histone proteins, wild-type (wt) p53 is particularly notable for the critical role that acetylation and methylation play in regulating its stability and function. Although with opposite outcomes, these post-translational modifications (PTMs) can also affect mutant forms of p53 (mutp53), which are frequently detected in cancers. These proteins may acquire oncogenic properties, activating signaling pathways that promote carcinogenesis. Acetylation activates wtp53, while this PTM has been shown to destabilize mutp53, reducing cancer aggressiveness and improving the efficacy of anticancer therapies. In this study, we investigated the possibility of targeting mutp53 in pancreatic cancer cells by using a combination of EZH2 and HDAC inhibitors. Methods: Western blotting, qRT-PCR, and ChIP experiments were performed to address this question. Results: We found that the EZH2 inhibitor Valemetostat (DS) in combination with the histone deacetylase inhibitor SAHA displaced the SET/TAF-Iβ oncoprotein from mutp53 and increased its interaction with the acetyltransferase p300, which was responsible for p53 acetylation. Moreover, mutp53 was downregulated, p21 was upregulated, and CHK1 was reduced, increasing DNA damage and leading to a stronger impairment of pancreatic cancer cell survival compared with single-agent treatments. Conclusions: Our results reveal that combining epigenetic drugs such as Valemetostat and SAHA could be exploited to target mutp53 and improve the outcome of treatments for aggressive tumors harboring it, such as in pancreatic cancer. Full article

Given the limited knowledge of the effect of post-translational modifications (PTMs) on protein structure, in this study we investigated whether introducing one-to-three RA-related PTMs into the α-fibrin (617–631) peptide influences the conformation and structure of the peptide antigen that could be responsible for the autoantibody recognition. Ten peptides containing a different number of PTMs within their primary structure were synthesized and their recognition by sera from RA patients was analyzed. The conformation of the peptides was studied by circular dichroism (CD) and the structure of the most relevant antigenic peptides was determined by nuclear magnetic resonance (NMR) and enhanced-sampling molecular dynamics (MD). Although peptides containing citrulline (Cit) showed a higher degree of binding to AMPAs than peptides containing only homocitrulline and/or acetyl-lysine, the latter were able to bind to AMPAs in sera that showed a small response to peptides with Cit, with the response being different depending on the position of each PTM. CD and NMR analyses indicated a series of half-turn conformations in the Lys620-Arg630 region. MD simulations generated a set of conformations compatible with the NMR NOEs. The effect of the PTMs was observed in intra-molecular contacts, hydrogen bonds and van der Waals interactions, generating more collapsed conformations. Differences in autoantibody reactivity between peptides bearing different PTMs within their primary structures are noted. Peptides with PTMs adopt different conformations than unmodified peptides, probably due to the lower net charge of peptides with multiple PTMs, which may explain their recognition by autoantibodies. Full article

Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular disease (CVD) that cannot be fully explained by traditional cardiometabolic risk factors. The observed ‘lipid paradox’, where RA patients with lower total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels exhibit higher CVD risk, may be attributed to post-translational modifications (PTMs). These lipoprotein PTMs likely arise from inflammatory pathways. While PTMs like citrullination and carbamylation are well recognized in RA joint pathology, their occurrence in other protein compartments and their role in CVD have been less well explored. This scoping review summarizes the current literature on PTMs of lipoproteins, including oxidation, nitration, carbamylation, and citrullination, and their impacts on CVD in RA. We also discuss immune responses to these PTMs, their interactions with scavenger receptors, and the effects of disease-modifying antirheumatic drugs. Further research on PTMs may uncover new pathways linking autoimmunity, inflammation, and vascular damage, offering novel diagnostic and therapeutic opportunities for RA-associated CVD. Full article

Post-translational modifications (PTMs) of proteins, as the core mechanism for dynamically regulating follicular development, affect the maintenance of mammalian fertility by precisely coordinating granulosa cell–oocyte interaction, metabolic reprogramming, and epigenetic remodeling. Dysregulation of these modifications directly contributes to major reproductive diseases, including polycystic ovary syndrome (PCOS) and premature ovarian insufficiency (POI). Post-translational modifications regulate follicular development through intricate mechanisms. Thus, this review systematically synthesizes recent advances in PTMs, encompassing traditional ones such as phosphorylation, ubiquitination, and acetylation, alongside emerging modifications including lactylation, SUMOylation, and ISGylation, thereby constructing a more comprehensive PTM landscape of follicular development. Furthermore, this study dissects the molecular interaction networks of these PTMs during follicular activation, maturation, and ovulation, and uncovers the common mechanisms through which PTM dysregulation contributes to pathological conditions, including hyperandrogenism in PCOS and follicular depletion in POI. Finally, this review ultimately provides a theoretical basis for improving livestock reproductive efficiency and precise intervention in clinical ovarian diseases. Full article

Lactylation, a recently identified post-translational modification (PTM) triggered by excessive lactate accumulation, has emerged as a crucial regulator linking metabolic reprogramming to pathological processes in liver diseases. In hepatic contexts, aberrant lactylation contributes to a range of pathological processes, including inflammation, dysregulation of lipid metabolism, angiogenesis, and fibrosis. Importantly, lactylation has been shown to impact tumor growth, metastasis, and therapy resistance by modulating oncogene expression, metabolic adaptation, stemness, angiogenesis, and altering the tumor microenvironment (TME). This review synthesizes current knowledge on the biochemical mechanisms of lactylation, encompassing both enzymatic and non-enzymatic pathways, and its roles in specific liver diseases. From a therapeutic perspective, targeting lactate availability and transport, as well as the enzymes regulating lactylation, has demonstrated promise in preclinical models. Additionally, combinatorial approaches and natural compounds have shown efficacy in disrupting lactylation-driven pathways, providing insights into future research directions for hepatic diseases. Although the emerging role of lactylation is gaining attention, its spatiotemporal dynamics and potential for clinical translation are not yet well comprehended. This review aims to synthesize the multifaceted roles of lactylation, thereby bridging mechanistic insights with actionable therapeutic strategies for liver diseases. Full article

Lysine succinylation is a recently discovered post-translational protein modification, the process of which requires the participation of various enzymes. The close association between cancer and protein post-translational modifications (PTMs), such as acetylation and phosphorylation, has been extensively investigated and well-established. In recent years, growing attention has been directed toward the role of succinylation in cancer progression. Accumulating evidence demonstrates that protein succinylation and desuccinylation play critical roles in promoting the development of various cancers, including lung, prostate, and renal cancers. Notably, the primary substrates undergoing succinylation are non-histone proteins. Therefore, elucidating the functions of cancer-related succinylated proteins is essential for identifying novel therapeutic targets. This review comprehensively summarizes current research advances regarding protein succinylation in common cancers and discusses the progress in developing succinylation-targeting drugs. Specifically, we focus on the molecular mechanisms by which succinylation regulates cancer progression, along with the identification of key succinylation sites. Our discussion aims to provide valuable insights for future research and the development of innovative cancer treatments. Full article

Post-translational modifications (PTMs) govern a multitude of protein functions within the cell, surpassing the basic function(s) encoded directly within the amino acid sequence. Despite the historical discovery of PTMs dating back over a century, recent technological advancements have facilitated the rapid expansion of the known PTM landscape. However, the elucidation of enzyme–substrate relationships responsible for PTMs, particularly for those less studied, remains a challenging endeavor. This review provides an extensive overview of methods employed in the discovery of enzyme-specific substrates for PTM catalysis. Beginning with traditional experimental approaches rooted in chemistry, biochemistry and cell biology, this review progresses to recently developed computational strategies tailored for identifying enzyme–substrate interactions. The analysis reflects on the remarkable progress achieved in PTM research to date, underscoring the increasing role of computational and high-throughput techniques in expediting enzyme–substrate discovery. Furthermore, it highlights the potential of artificial intelligence to revolutionize PTM research and emphasizes the importance of unbiased high-throughput analysis in advancing our understanding of PTM networks. Ultimately, the review advocates for the integration of sophisticated computational strategies with experimental techniques to unravel the complex enzyme–substrate networks governing PTM-mediated cellular processes. Full article

Histone post-translational modifications (PTMs) have emerged as promising epigenetic biomarkers with increasing forensic relevance. Unlike conventional genetic markers such as short tandem repeats (STRs), histone modifications can offer additional layers of biological information, capturing individual-specific regulatory states and remaining detectable even in degraded forensic samples. This review highlights recent advances in understanding histone PTMs in forensic contexts, focusing on three key domains: analysis of degraded biological evidence, differentiation of monozygotic (MZ) twins, and postmortem interval (PMI) estimation. We summarize experimental findings from human cadavers, animal models, and typical forensic samples including bone, blood, and muscle, illustrating the stability and diagnostic potential of marks such as H3K4me3, H3K27me3, and γ-H2AX. Emerging technologies including CUT&Tag, MALDI imaging, and nanopore-based sequencing offer novel opportunities to profile histone modifications at high resolution and low input. Despite technical challenges, these findings support the feasibility of histone-based biomarkers as complementary tools for forensic identification and temporal analysis. Future work should prioritize methodological standardization, inter-laboratory validation, and integration into forensic workflows. However, the forensic applicability of these modifications remains largely unvalidated, and further studies are required to assess their reliability in casework contexts. Full article

Schizophrenia (SCZ) is a complex psychiatric disorder with heterogeneous molecular underpinnings that remain poorly resolved by conventional single-omics approaches, limiting biomarker discovery and mechanistic insights. To address this gap, we applied an artificial intelligence (AI)-driven multi-omics framework to an open access dataset comprising plasma proteomics, post-translational modifications (PTMs), and metabolomics to systematically dissect SCZ pathophysiology. In a cohort of 104 individuals, comparative analysis of 17 machine learning models revealed that multi-omics integration significantly enhanced classification performance, reaching a maximum AUC of 0.9727 (95% CI: 0.8889–1.000) using LightGBMXT, compared to 0.9636 (95% CI: 0.8636–1.0000) with CNNBiLSTM for proteomics alone. Interpretable feature prioritization identified carbamylation at immunoglobulin-constant region sites IGKC_K20 and IGHG1_K8, alongside oxidation of coagulation factor F10 at residue M8, as key discriminative molecular events. Functional analyses identified significantly enriched pathways including complement activation, platelet signaling, and gut microbiota-associated metabolism. Protein interaction networks further implicated coagulation factors F2, F10, and PLG, as well as complement regulators CFI and C9, as central molecular hubs. The clustering of these molecules highlights a potential axis linking immune activation, blood coagulation, and tissue homeostasis, biological domains increasingly recognized in psychiatric disorders. These results implicate immune–thrombotic dysregulation as a critical component of SCZ pathology, with PTMs of immune proteins serving as quantifiable disease indicators. Our work delineates a robust computational strategy for multi-omics integration into psychiatric research, offering biomarker candidates that warrant further validation for diagnostic and therapeutic applications. Full article

Botrytis cinerea is a highly versatile pathogenic fungus, causing significant damage across a wide range of plant species. A central focus of this review is the recent advances made through proteomics, an advanced molecular tool, in understanding the mechanisms of B. cinerea infection. Recent advances in mass spectrometry-based proteomics—including LC-MS/MS, iTRAQ, MALDI-TOF, and surface shaving—have enabled the in-depth characterization of B. cinerea subproteomes such as the secretome, surfactome, phosphoproteome, and extracellular vesicles, revealing condition-specific pathogenic mechanisms. Notably, in under a decade, the proportion of predicted proteins experimentally identified has increased from 10% to 52%, reflecting the rapid progress in proteomic capabilities. We explore how proteomic studies have significantly enhanced our knowledge of the fungus secretome and the role of extracellular vesicles (EVs), which play key roles in pathogenesis, by identifying secreted proteins—such as pH-responsive elements—that may serve as biomarkers and therapeutic targets. These technologies have also uncovered fine regulatory mechanisms across multiple levels of the fungal proteome, including post-translational modifications (PTMs), the phosphomembranome, and the surfactome, providing a more integrated view of its infection strategy. Moreover, proteomic approaches have contributed to a better understanding of host–pathogen interactions, including aspects of the plant’s defensive responses. Furthermore, this review discusses how proteomic data have helped to identify metabolic pathways affected by novel, more environmentally friendly antifungal compounds. A further update on the advances achieved in the field of proteomics discovery for the organism under consideration is provided in this paper, along with a perspective on emerging tools and future developments expected to accelerate research and improve targeted intervention strategies. Full article

Over the past decade, the number and diversity of identified protein post-translational modifications (PTMs) have grown significantly. However, most PTMs occur at relatively low abundance, making selective enrichment of modified peptides essential. To address this, we developed a thermodynamic model describing the free beads enrichment in suspension enrichment process and derived a theoretical relationship between material dosage and analyte recovery. The model predicts a non-linear trend, with enrichment efficiency increasing up to an optimal dosage and declining thereafter—a pattern confirmed by experimental data. We validated the model using centrifugation-based enrichment for glycosylated peptides and magnetic-based enrichment for phosphorylated peptides. In both cases, the results aligned with theoretical predictions. Additionally, the optimal dosage varied among peptides with the same modification type, highlighting the importance of tailoring enrichment strategies. This study provides a solid theoretical and experimental basis for optimizing PTMs enrichment and advancing more sensitive, accurate, and efficient mass spectrometry-based proteomic workflows. Full article