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Frontiers in Immunology 2021Protein S-palmitoylation is a covalent and reversible lipid modification that specifically targets cysteine residues within many eukaryotic proteins. In mammalian... (Review)
Review
Protein S-palmitoylation is a covalent and reversible lipid modification that specifically targets cysteine residues within many eukaryotic proteins. In mammalian cells, the ubiquitous palmitoyltransferases (PATs) and serine hydrolases, including acyl protein thioesterases (APTs), catalyze the addition and removal of palmitate, respectively. The attachment of palmitoyl groups alters the membrane affinity of the substrate protein changing its subcellular localization, stability, and protein-protein interactions. Forty years of research has led to the understanding of the role of protein palmitoylation in significantly regulating protein function in a variety of biological processes. Recent global profiling of immune cells has identified a large body of S-palmitoylated immunity-associated proteins. Localization of many immune molecules to the cellular membrane is required for the proper activation of innate and adaptive immune signaling. Emerging evidence has unveiled the crucial roles that palmitoylation plays to immune function, especially in partitioning immune signaling proteins to the membrane as well as to lipid rafts. More importantly, aberrant PAT activity and fluctuations in palmitoylation levels are strongly correlated with human immunologic diseases, such as sensory incompetence or over-response to pathogens. Therefore, targeting palmitoylation is a novel therapeutic approach for treating human immunologic diseases. In this review, we discuss the role that palmitoylation plays in both immunity and immunologic diseases as well as the significant potential of targeting palmitoylation in disease treatment.
Topics: Acyltransferases; Adaptive Immunity; Animals; Humans; Immune System; Immune System Diseases; Immunity, Innate; Lipoylation; Protein Processing, Post-Translational; Proteins; Signal Transduction
PubMed: 34557182
DOI: 10.3389/fimmu.2021.661202 -
Journal of Proteome Research Jan 2021Protein -acylation (commonly known as palmitoylation) is a widespread reversible lipid modification, which plays critical roles in regulating protein localization,... (Review)
Review
Protein -acylation (commonly known as palmitoylation) is a widespread reversible lipid modification, which plays critical roles in regulating protein localization, activity, stability, and complex formation. The deregulation of protein -acylation contributes to many diseases such as cancer and neurodegenerative disorders. The past decade has witnessed substantial progress in proteomic analysis of protein -acylation, which significantly advanced our understanding of -acylation biology. In this review, we summarized the techniques for the enrichment of -acylated proteins or peptides, critically reviewed proteomic studies of protein -acylation at eight different levels, and proposed major challenges for the -acylproteomics field. In summary, proteome-scale analysis of protein -acylation comes of age and will play increasingly important roles in discovering new disease mechanisms, biomarkers, and therapeutic targets.
Topics: Acylation; Lipoylation; Protein S; Proteome; Proteomics
PubMed: 33253586
DOI: 10.1021/acs.jproteome.0c00409 -
Electrophoresis Mar 2021Globular proteins exhibit dielectrophoresis (DEP) responses in experiments where the applied field gradient factor ∇E appears far too small, according to standard DEP... (Review)
Review
Globular proteins exhibit dielectrophoresis (DEP) responses in experiments where the applied field gradient factor ∇E appears far too small, according to standard DEP theory, to overcome dispersive forces associated with the thermal energy kT of disorder. To address this a DEP force equation is proposed that replaces a previous empirical relationship between the macroscopic and microscopic forms of the Clausius-Mossotti factor. This equation relates the DEP response of a protein directly to the dielectric increment δε and decrement δε that characterize its β-dispersion at radio frequencies, and also indirectly to its intrinsic dipole moment by way of providing a measure of the protein's effective volume. A parameter Γ , taken as a measure of cross-correlated dipole interactions between the protein and its water molecules of hydration, is included in this equation. For 9 of the 12 proteins, for which an evaluation can presently be made, Γ has a value of ≈4600 ± 120. These conclusions follow an analysis of the failure of macroscopic dielectric mixture (effective medium) theories to predict the dielectric properties of solvated proteins. The implication of a polarizability greatly exceeding the intrinsic value for a protein might reflect the formation of relaxor ferroelectric nanodomains in its hydration shell.
Topics: Electric Conductivity; Electrophoresis; Models, Chemical; Proteins
PubMed: 33084076
DOI: 10.1002/elps.202000255 -
Journal of Biochemistry Feb 2021DNA replication is spatially and temporally regulated during S phase to execute efficient and coordinated duplication of entire genome. Various epigenomic mechanisms... (Review)
Review
DNA replication is spatially and temporally regulated during S phase to execute efficient and coordinated duplication of entire genome. Various epigenomic mechanisms operate to regulate the timing and locations of replication. Among them, Rif1 plays a major role to shape the 'replication domains' that dictate which segments of the genome are replicated when and where in the nuclei. Rif1 achieves this task by generating higher-order chromatin architecture near nuclear membrane and by recruiting a protein phosphatase. Rif1 is a G4 binding protein, and G4 binding activity of Rif1 is essential for replication timing regulation in fission yeast. In this article, we first summarize strategies by which cells regulate their replication timing and then describe how Rif1 and its interaction with G4 contribute to regulation of chromatin architecture and replication timing.
Topics: Animals; Carrier Proteins; Cell Cycle; Cell Nucleus; Chromatin; DNA Replication; DNA Replication Timing; G-Quadruplexes; Humans; Protein Binding; Repressor Proteins; S Phase; Saccharomyces cerevisiae Proteins; Schizosaccharomyces; Schizosaccharomyces pombe Proteins; Telomere-Binding Proteins
PubMed: 33169133
DOI: 10.1093/jb/mvaa128 -
Current Genetics Apr 2021Yeast is one of the best-understood biological systems for genetic research. Over the last 40 years, geneticists have striven to search for homologues of tumor... (Review)
Review
Yeast is one of the best-understood biological systems for genetic research. Over the last 40 years, geneticists have striven to search for homologues of tumor suppressors in yeast to simplify cancer research. The star tumor suppressor p21, downstream target of p53, is one of the primary factors on the START point through negatively regulating CycD/E-CDK, the yeast counterpart Cln3-Cdk1. Not like yeast Whi5 that was identified as the analog of the retinoblastoma tumor suppressor protein (Rb) and hence promoted to uncover the mechanism of its cancer suppression, homologue of p21 had not been found in yeast. Our lab identified Cip1 in budding yeast as a novel negative regulator of G1-Cdk1 and proposed that Cip1 is an analog of human p21. Recently, we demonstrated a dual repressive function of Cip1 on START timing via the redundant Cln3 and Ccr4 pathways. This work in yeast may help clarify the complex regulation in human p53-p21 signaling cascade. In this review, we will discuss the yeast paralogs of star tumor suppressors in the control of G1/S transition and present the new findings in this field.
Topics: CDC2 Protein Kinase; Cell Cycle Proteins; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; G1 Phase; Humans; Repressor Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Tumor Suppressor Protein p53; Tumor Suppressor Proteins
PubMed: 33175222
DOI: 10.1007/s00294-020-01126-3 -
Biomolecules May 2023Initially, protein aggregates were regarded as a sign of a pathological state of the cell. Later, it was found that these assemblies are formed in response to stress,... (Review)
Review
Initially, protein aggregates were regarded as a sign of a pathological state of the cell. Later, it was found that these assemblies are formed in response to stress, and that some of them serve as signalling mechanisms. This review has a particular focus on how intracellular protein aggregates are related to altered metabolism caused by different glucose concentrations in the extracellular environment. We summarise the current knowledge of the role of energy homeostasis signalling pathways in the consequent effect on intracellular protein aggregate accumulation and removal. This covers regulation at different levels, including elevated protein degradation and proteasome activity mediated by the Hxk2 protein, the enhanced ubiquitination of aberrant proteins through Torc1/Sch9 and Msn2/Whi2, and the activation of autophagy mediated through genes. Finally, certain proteins form reversible biomolecular aggregates in response to stress and reduced glucose levels, which are used as a signalling mechanism in the cell, controlling major primary energy pathways related to glucose sensing.
Topics: Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Caloric Restriction; Protein Aggregates; Glucose; DNA-Binding Proteins; Transcription Factors
PubMed: 37238710
DOI: 10.3390/biom13050841 -
Journal of Medicinal Chemistry Apr 2022Protein -nitrosation (SNO), a posttranslational modification (PTM) of cysteine (Cys) residues elicited by nitric oxide (NO), regulates a wide range of protein functions.... (Review)
Review
Protein -nitrosation (SNO), a posttranslational modification (PTM) of cysteine (Cys) residues elicited by nitric oxide (NO), regulates a wide range of protein functions. As a crucial form of redox-based signaling by NO, SNO contributes significantly to the modulation of physiological functions, and SNO imbalance is closely linked to pathophysiological processes. Site-specific identification of the SNO protein is critical for understanding the underlying molecular mechanisms of protein function regulation. Although careful verification is needed, SNO modification data containing numerous functional proteins are a potential research direction for druggable target identification and drug discovery. Undoubtedly, SNO-related research is meaningful not only for the development of NO donor drugs but also for classic target-based drug design. Herein, we provide a comprehensive summary of SNO, including its origin and transport, identification, function, and potential contribution to drug discovery. Importantly, we propose new views to develop novel therapies based on potential protein SNO-sourced targets.
Topics: Cysteine; Nitric Oxide; Nitrosation; Protein Processing, Post-Translational; Protein S; Proteins
PubMed: 35412827
DOI: 10.1021/acs.jmedchem.1c02194 -
Nature Structural & Molecular Biology Jun 2022Cohesin is a DNA translocase that is instrumental in the folding of the genome into chromatin loops, with functional consequences on DNA-related processes. Chromatin...
Cohesin is a DNA translocase that is instrumental in the folding of the genome into chromatin loops, with functional consequences on DNA-related processes. Chromatin loop length and organization likely depend on cohesin processivity, translocation rate and stability on DNA. Here, we investigate and provide a comprehensive overview of the roles of various cohesin regulators in tuning chromatin loop expansion in budding yeast Saccharomyces cerevisiae. We demonstrate that Scc2, which stimulates cohesin ATPase activity, is also essential for cohesin translocation, driving loop expansion in vivo. Smc3 acetylation during the S phase counteracts this activity through the stabilization of Pds5, which finely tunes the size and stability of loops in G2.
Topics: Acetylation; Cell Cycle Proteins; Chromatin; Chromosomal Proteins, Non-Histone; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Cohesins
PubMed: 35710835
DOI: 10.1038/s41594-022-00780-0 -
Journal of Thrombosis and Haemostasis :... Apr 2023The complex reactions of blood coagulation are balanced by several natural anticoagulants resulting in tuned hemostasis. During several decades, the knowledge base of... (Review)
Review
The complex reactions of blood coagulation are balanced by several natural anticoagulants resulting in tuned hemostasis. During several decades, the knowledge base of the natural anticoagulants has greatly increased and we have also learned about antiinflammatory and cytoprotective activities expressed by antithrombin and activated protein C (APC). Some coagulation proteins have also been found to function as anticoagulants; e.g., thrombin when bound to thrombomodulin activates protein C. Another example is factor V (FV), which in addition to being a procofactor to FVa has emerged as an anticoagulant. The discovery of APC resistance, caused by FVLeiden, as a thrombosis risk factor resulted in the identification of FV as an APC cofactor working in synergy with protein S in the regulation of FVIIIa in the Xase complex. More recently, a natural anticoagulant FV splice isoform (FV-Short) was discovered when investigating the East Texas bleeding disorder. In FV-Short, the truncated B domain exposes a high-affinity binding site for tissue factor pathway inhibitor alpha (TFPIα), and together with protein S a high-affinity trimolecular complex is generated. The FXa-inhibitory activity of TFPIα is synergistically stimulated by FV-Short and protein S. The circulating FV-Short/protein S/TFPIα complex concentration is normally low (≈0.2 nM) but provides an anticoagulant threshold. In the East Texas bleeding, the concentration of the complex, and thus the threshold, is increased 10-fold, which results in bleeding manifestations. The anticoagulant properties of FV were discovered during investigations of individual patients and follow the great tradition of bed-to-bench and bench-to-bed research in the coagulation field.
Topics: Humans; Anticoagulants; Protein C; Factor V; Protein S; Blood Coagulation
PubMed: 36746318
DOI: 10.1016/j.jtha.2023.01.033 -
Thrombosis Research Oct 2023Thrombin, the enzyme which converts fibrinogen into a fibrin clot, is produced by the prothrombinase complex, composed of factor Xa (FXa) and factor Va (FVa)....
INTRODUCTION
Thrombin, the enzyme which converts fibrinogen into a fibrin clot, is produced by the prothrombinase complex, composed of factor Xa (FXa) and factor Va (FVa). Down-regulation of this process is critical, as excess thrombin can lead to life-threatening thrombotic events. FXa and FVa are inhibited by the anticoagulants tissue factor pathway inhibitor alpha (TFPIα) and activated protein C (APC), respectively, and their common cofactor protein S (PS). However, prothrombinase is resistant to either of these inhibitory systems in isolation.
MATERIALS AND METHODS
We hypothesized that these anticoagulants function best together, and tested this hypothesis using purified proteins and plasma-based systems.
RESULTS
In plasma, TFPIα had greater anticoagulant activity in the presence of APC and PS, maximum PS activity required both TFPIα and APC, and antibodies against TFPI and APC had an additive procoagulant effect, which was mimicked by an antibody against PS alone. In purified protein systems, TFPIα dose-dependently inhibited thrombin activation by prothrombinase, but only in the presence of APC, and this activity was enhanced by PS. Conversely, FXa protected FVa from cleavage by APC, even in the presence of PS, and TFPIα reversed this protection. However, prothrombinase assembled on platelets was still protected from inhibition, even in the presence of TFPIα, APC, and PS.
CONCLUSIONS
We propose a model of prothrombinase inhibition through combined targeting of both FXa and FVa, and that this mechanism enables down-regulation of thrombin activation outside of a platelet clot. Platelets protect prothrombinase from inhibition, however, supporting a procoagulant environment within the clot.
Topics: Humans; Anticoagulants; Blood Coagulation; Factor V; Factor Va; Factor Xa; Protein C; Protein S; Thrombin; Thromboplastin
PubMed: 37660436
DOI: 10.1016/j.thromres.2023.08.012