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The FEBS Journal Jun 2022Histones constitute the primary protein building blocks of the chromatin and play key roles in the dynamic control of chromatin compaction and epigenetic regulation.... (Review)
Review
Histones constitute the primary protein building blocks of the chromatin and play key roles in the dynamic control of chromatin compaction and epigenetic regulation. Histones are regulated by intricate mechanisms that alter their functionality and stability, thereby expanding the regulation of chromatin-transacting processes. As such, histone degradation is tightly regulated to provide spatiotemporal control of cellular histone abundance. While several mechanisms have been implicated in controlling histone stability, here, we discuss proteasome-dependent degradation of histones and the protein modifications that are associated with it. We then highlight specific cellular and physiological states that are associated with altered histone degradation by cellular proteasomes.
Topics: Cell Plasticity; Chromatin; Epigenesis, Genetic; Histones; Proteasome Endopeptidase Complex
PubMed: 33914417
DOI: 10.1111/febs.15903 -
Current Opinion in Structural Biology Apr 2021The majority of regulated protein degradation in eukaryotes is accomplished by the 26S proteasome, the large proteolytic complex responsible for removing regulatory... (Review)
Review
The majority of regulated protein degradation in eukaryotes is accomplished by the 26S proteasome, the large proteolytic complex responsible for removing regulatory proteins and damaged proteins. Proteins are targeted to the proteasome by ubiquitination, and degradation is initiated at a disordered region within the protein. The ability of the proteasome to precisely select which proteins to break down is necessary for cellular functioning. Recent studies reveal the subtle mechanisms of substrate recognition by the proteasome - diverse ubiquitin chains can act as potent proteasome targeting signals, ubiquitin receptors function uniquely and cooperatively, and modification of initiation regions modulate degradation. Here, we summarize recent findings illuminating the nature of substrate recognition by the proteasome.
Topics: Proteasome Endopeptidase Complex; Proteolysis; Ubiquitin; Ubiquitination
PubMed: 33296738
DOI: 10.1016/j.sbi.2020.10.010 -
Biomolecules Mar 2020This review provides information on the structure of estrogen receptors (ERs), their localization and functions in mammalian cells. Additionally, the structure of... (Review)
Review
This review provides information on the structure of estrogen receptors (ERs), their localization and functions in mammalian cells. Additionally, the structure of proteasomes and mechanisms of protein ubiquitination and cleavage are described. According to the modern concept, the ubiquitin proteasome system (UPS) is involved in the regulation of the activity of ERs in several ways. First, UPS performs the ubiquitination of ERs with a change in their functional activity. Second, UPS degrades ERs and their transcriptional regulators. Third, UPS affects the expression of ER genes. In addition, the opportunity of the regulation of proteasome functioning by ERs-in particular, the expression of immune proteasomes-is discussed. Understanding the complex mechanisms underlying the regulation of ERs and proteasomes has great prospects for the development of new therapeutic agents that can make a significant contribution to the treatment of diseases associated with the impaired function of these biomolecules.
Topics: Animals; Cysteine Endopeptidases; Gene Expression Regulation; Humans; Proteasome Endopeptidase Complex; Receptors, Estrogen; Ubiquitin; Ubiquitin-Protein Ligase Complexes
PubMed: 32224970
DOI: 10.3390/biom10040500 -
The Journal of Physical Chemistry. B Jul 2020The proteasome is a key protease in the eukaryotic cells which is responsible for various important cellular processes such as the control of the cell cycle, immune...
The proteasome is a key protease in the eukaryotic cells which is responsible for various important cellular processes such as the control of the cell cycle, immune responses, protein homeostasis, inflammation, apoptosis, and the response to proteotoxic stress. Acting as a major molecular machine for protein degradation, proteasome first identifies damaged or obsolete regulatory proteins by attaching ubiquitin chains and subsequently utilizes conserved pore loops of the heterohexameric ring of AAA+ (ATPases associated with diverse cellular activities) to pull and mechanically unfold and translocate the misfolded protein to the active site for proteolysis. A detailed knowledge of the reaction mechanism for this proteasomal proteolysis is of central importance, both for fundamental understanding and for drug discovery. The present study investigates the mechanism of the proteolysis by the proteasome with full consideration of the protein's flexibility and its impact on the reaction free energy. Major attention is paid to the role of the protein electrostatics in determining the activation barriers. The reaction mechanism is studied by considering a small artificial fluorogenic peptide substrate (Suc-LLVY-AMC) and evaluating the activation barriers and reaction free energies for the acylation and deacylation steps, by using the empirical valence bond method. Our results shed light on the proteolysis mechanism and thus should be important for further studies of the proteasome action.
Topics: Adenosine Triphosphatases; Cytoplasm; Proteasome Endopeptidase Complex; Proteolysis; Ubiquitin
PubMed: 32498514
DOI: 10.1021/acs.jpcb.0c04435 -
Bioinformatics (Oxford, England) Dec 2021The proteasome is the main proteolytic machine for targeted protein degradation in archaea and eukaryotes. While some bacteria also possess the proteasome, most of them...
MOTIVATION
The proteasome is the main proteolytic machine for targeted protein degradation in archaea and eukaryotes. While some bacteria also possess the proteasome, most of them contain a simpler and more specialized homolog, the heat shock locus V protease. In recent years, three further homologs of the proteasome core subunits have been characterized in prokaryotes: Anbu, BPH and connectase. With the inclusion of these members, the family of proteasome-like proteins now exhibits a range of architectural and functional forms, from the canonical proteasome, a barrel-shaped protease without pronounced intrinsic substrate specificity, to the monomeric connectase, a highly specific protein ligase.
RESULTS
We employed systematic sequence searches to show that we have only seen the tip of the iceberg so far and that beyond the hitherto known proteasome homologs lies a wealth of distantly related, uncharacterized homologs. We describe a total of 22 novel proteasome homologs in bacteria and archaea. Using sequence and structure analysis, we analyze their evolutionary history and assess structural differences that may modulate their function. With this initial description, we aim to stimulate the experimental investigation of these novel proteasome-like family members.
AVAILABILITY AND IMPLEMENTATION
The protein sequences in this study are searchable in the MPI Bioinformatics Toolkit (https://toolkit.tuebingen.mpg.de) with ProtBLAST/PSI-BLAST and with HHpred (database 'proteasome_homologs'). The following data are available at https://data.mendeley.com/datasets/t48yhff7hs/3: (i) sequence alignments for each proteasome-like homolog, (ii) the coordinates for their structural models and (iii) a cluster-map file, which can be navigated interactively in CLANS and gives direct access to all the sequences in this study.
SUPPLEMENTARY INFORMATION
Supplementary data are available at Bioinformatics online.
Topics: Proteasome Endopeptidase Complex; Proteins; Amino Acid Sequence; Bacteria; Biological Evolution; Archaea
PubMed: 34323935
DOI: 10.1093/bioinformatics/btab558 -
Cell Reports Aug 2020The proteasome is the main proteolytic system for targeted protein degradation in the cell and is fine-tuned according to cellular needs. Here, we demonstrate that...
The proteasome is the main proteolytic system for targeted protein degradation in the cell and is fine-tuned according to cellular needs. Here, we demonstrate that mitochondrial dysfunction and concomitant metabolic reprogramming of the tricarboxylic acid (TCA) cycle reduce the assembly and activity of the 26S proteasome. Both mitochondrial mutations in respiratory complex I and treatment with the anti-diabetic drug metformin impair 26S proteasome activity. Defective 26S assembly is reversible and can be overcome by supplementation of aspartate or pyruvate. This metabolic regulation of 26S activity involves specific regulation of proteasome assembly factors via the mTORC1 pathway. Of note, reducing 26S activity by metformin confers increased resistance toward the proteasome inhibitor bortezomib, which is reversible upon pyruvate supplementation. Our study uncovers unexpected consequences of defective mitochondrial metabolism for proteasomal protein degradation in the cell, which has important pathophysiological and therapeutic implications.
Topics: Humans; Mitochondria; Proteasome Endopeptidase Complex
PubMed: 32846138
DOI: 10.1016/j.celrep.2020.108059 -
Biochimica Et Biophysica Acta. Proteins... Mar 2021In eukaryotic cells, the ubiquitin-proteasome system serves to remove proteins that are either dysfunctional or no longer needed. The 26S proteasome is a 2.5 MDa... (Review)
Review
In eukaryotic cells, the ubiquitin-proteasome system serves to remove proteins that are either dysfunctional or no longer needed. The 26S proteasome is a 2.5 MDa multisubunit complex comprising the 20S core particle, where degradation is executed, and one or two regulatory particles which prepare substrates for degradation. Whereas the 20S core particles of several species had been studied extensively by X-ray crystallography, the 26S holocomplex structure had remained elusive for a long time. Recent advances in single-particle cryo-electron microscopy have changed the situation and provided atomic resolution models of this intriguing molecular machine and its dynamics. Besides, cryo-electron tomography enables structural studies in situ, providing molecular resolution images of macromolecules inside pristinely preserved cellular environments. This has greatly contributed to our understanding of proteasome dynamics in the context of cells.
Topics: Cryoelectron Microscopy; Crystallography, X-Ray; Proteasome Endopeptidase Complex; Protein Conformation; Subcellular Fractions
PubMed: 33321258
DOI: 10.1016/j.bbapap.2020.140583 -
Frontiers in Cellular and Infection... 2021Ubiquitin-proteasome mediated protein turnover is an important regulatory mechanism of cellular function in eukaryotes. Extensive studies have linked the... (Review)
Review
Ubiquitin-proteasome mediated protein turnover is an important regulatory mechanism of cellular function in eukaryotes. Extensive studies have linked the ubiquitin-proteasome system (UPS) to human diseases, and an array of proteasome inhibitors have been successfully developed for cancer therapy. Although still an emerging field, research on UPS regulation of fungal development and virulence has been rapidly advancing and has generated considerable excitement in its potential as a target for novel drugs. In this review, we summarize UPS composition and regulatory function in pathogenic fungi, especially in stress responses, host adaption, and fungal pathogenesis. Emphasis will be given to UPS regulation of pathogenic factors that are important for fungal pathogenesis. We also discuss future potential therapeutic strategies for fungal infections based on targeting UPS pathways.
Topics: Fungi; Humans; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Proteolysis; Ubiquitin
PubMed: 34858882
DOI: 10.3389/fcimb.2021.774613 -
Biomolecules May 2021Although ubiquitination is widely assumed to be the only regulated step in the ubiquitin-proteasome pathway, recent studies have demonstrated several important... (Review)
Review
Although ubiquitination is widely assumed to be the only regulated step in the ubiquitin-proteasome pathway, recent studies have demonstrated several important mechanisms that regulate the activities of the 26S proteasome. Most proteasomes in cells are inactive but, upon binding a ubiquitinated substrate, become activated by a two-step mechanism requiring an association of the ubiquitin chain with Usp14 and then a loosely folded protein domain with the ATPases. The initial activation step is signaled by Usp14's UBL domain, and many UBL-domain-containing proteins (e.g., Rad23, Parkin) also activate the proteasome. ZFAND5 is a distinct type of activator that binds ubiquitin conjugates and the proteasome and stimulates proteolysis during muscle atrophy. The proteasome's activities are also regulated through subunit phosphorylation. Agents that raise cAMP and activate PKA stimulate within minutes Rpn6 phosphorylation and enhance the selective degradation of short-lived proteins. Likewise, hormones, fasting, and exercise, which raise cAMP, activate proteasomes and proteolysis in target tissues. Agents that raise cGMP and activate PKG also stimulate 26S activities but modify different subunit(s) and stimulate also the degradation of long-lived cell proteins. Both kinases enhance the selective degradation of aggregation-prone proteins that cause neurodegenerative diseases. These new mechanisms regulating proteolysis thus have clear physiological importance and therapeutic potential.
Topics: Animals; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP-Dependent Protein Kinases; DNA Repair Enzymes; DNA-Binding Proteins; Enzyme Activation; Humans; Muscular Atrophy; Neurodegenerative Diseases; Proteasome Endopeptidase Complex; Proteins; Proteolysis; Ubiquitin Thiolesterase; Ubiquitin-Protein Ligases
PubMed: 34067263
DOI: 10.3390/biom11060779 -
Trends in Genetics : TIG Feb 2021The key to a healthy mammalian cell lies in properly functioning proteolytic machineries called proteasomes. The proteasomes are multisubunit complexes that catalyze the... (Review)
Review
The key to a healthy mammalian cell lies in properly functioning proteolytic machineries called proteasomes. The proteasomes are multisubunit complexes that catalyze the degradation of unwanted proteins and also control half-lives of key cellular regulatory factors. Aberrant proteasome activity is often associated with human diseases such as cancer and neurodegeneration, and so an in-depth understanding of how it is regulated has implications for potential disease interventions. Transcriptional regulation of the proteasome can dictate its abundance and also influence its function, assembly, and location. This ensures proper proteasomal activity in response to developmental cues and to physiological conditions such as starvation and oxidative stress. In this review, we highlight and discuss the roles of the transcription factors that are involved in the regulation of the mammalian proteasome.
Topics: Animals; Humans; Mammals; Neoplasms; Oxidative Stress; Proteasome Endopeptidase Complex; Proteins; Proteolysis; Transcription Factors; Transcription, Genetic
PubMed: 32988635
DOI: 10.1016/j.tig.2020.09.005