scholarly journals Sperm proteasome and fertilization

Reproduction ◽  
2011 ◽  
Vol 142 (1) ◽  
pp. 1-14 ◽  
Author(s):  
Peter Sutovsky
Keyword(s):  
Current Knowledge ◽  
Sea Urchins ◽  
Ubiquitin Proteasome System ◽  
26S Proteasome ◽  
Deubiquitinating Enzymes ◽  
Human Reproductive ◽  
Sperm Penetration ◽  
Covalently Linked ◽  
Enzymatic Machinery ◽  
Sperm Receptor

The omnipresent ubiquitin–proteasome system (UPS) is an ATP-dependent enzymatic machinery that targets substrate proteins for degradation by the 26S proteasome by tagging them with an isopeptide chain composed of covalently linked molecules of ubiquitin, a small chaperone protein. The current knowledge of UPS involvement in the process of sperm penetration through vitelline coat (VC) during human and animal fertilization is reviewed in this study, with attention also being given to sperm capacitation and acrosome reaction/exocytosis. In ascidians, spermatozoa release ubiquitin-activating and conjugating enzymes, proteasomes, and unconjugated ubiquitin to first ubiquitinate and then degrade the sperm receptor on the VC; in echinoderms and mammals, the VC (zona pellucida/ZP in mammals) is ubiquitinated during oogenesis and the sperm receptor degraded during fertilization. Various proteasomal subunits and associated enzymes have been detected in spermatozoa and localized to sperm acrosome and other sperm structures. By using specific fluorometric substrates, proteasome-specific proteolytic and deubiquitinating activities can be measured in live, intact spermatozoa and in sperm protein extracts. The requirement of proteasomal proteolysis during fertilization has been documented by the application of various proteasome-specific inhibitors and antibodies. A similar effect was achieved by depletion of sperm-surface ATP. Degradation of VC/ZP-associated sperm receptor proteins by sperm-borne proteasomes has been demonstrated in ascidians and sea urchins. On the applied side, polyspermy has been ameliorated by modulating sperm-associated deubiquitinating enzymes. Diagnostic and therapeutic applications could emerge in human reproductive medicine. Altogether, the studies on sperm proteasome indicate that animal fertilization is controlled in part by a unique, gamete associated, extracellular UPS.

scholarly journals Co-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome

Biomolecules ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1141 ◽  
Author(s):  
Amanda B. Abildgaard ◽  
Sarah K. Gersing ◽  
Sven Larsen-Ledet ◽  
Sofie V. Nielsen ◽  
Amelie Stein ◽  
...  
Keyword(s):  
Protein Quality ◽  
Current Knowledge ◽  
Ubiquitin Proteasome System ◽  
26S Proteasome ◽  
Misfolded Proteins ◽  
Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Ubiquitin Proteasome ◽  
Underlying Mechanisms ◽  
The Individual

Protein homeostasis (proteostasis) is essential for the cell and is maintained by a highly conserved protein quality control (PQC) system, which triages newly synthesized, mislocalized and misfolded proteins. The ubiquitin-proteasome system (UPS), molecular chaperones, and co-chaperones are vital PQC elements that work together to facilitate degradation of misfolded and toxic protein species through the 26S proteasome. However, the underlying mechanisms are complex and remain partly unclear. Here, we provide an overview of the current knowledge on the co-chaperones that directly take part in targeting and delivery of PQC substrates for degradation. While J-domain proteins (JDPs) target substrates for the heat shock protein 70 (HSP70) chaperones, nucleotide-exchange factors (NEFs) deliver HSP70-bound substrates to the proteasome. So far, three NEFs have been established in proteasomal delivery: HSP110 and the ubiquitin-like (UBL) domain proteins BAG-1 and BAG-6, the latter acting as a chaperone itself and carrying its substrates directly to the proteasome. A better understanding of the individual delivery pathways will improve our ability to regulate the triage, and thus regulate the fate of aberrant proteins involved in cell stress and disease, examples of which are given throughout the review.

scholarly journals Unstructured Biology of Proteins from Ubiquitin-Proteasome System: Roles in Cancer and Neurodegenerative Diseases

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 796 ◽  
Author(s):  
Kundlik Gadhave ◽  
Prateek Kumar ◽  
Shivani Kapuganti ◽  
Vladimir Uversky ◽  
Rajanish Giri
Keyword(s):  
Intrinsically Disordered Protein ◽  
Intrinsic Disorder ◽  
Ubiquitin Proteasome System ◽  
Cellular Protein ◽  
26S Proteasome ◽  
Deubiquitinating Enzymes ◽  
Intrinsically Disordered ◽  
Anti Cancer ◽  
Ubiquitin Proteasome ◽  
Dependent Protein

The 26S proteasome is a large (~2.5 MDa) protein complex consisting of at least 33 different subunits and many other components, which form the ubiquitin proteasomal system (UPS), an ATP-dependent protein degradation system in the cell. UPS serves as an essential component of the cellular protein surveillance machinery, and its dysfunction leads to cancer, neurodegenerative and immunological disorders. Importantly, the functions and regulations of proteins are governed by the combination of ordered regions, intrinsically disordered protein regions (IDPRs) and molecular recognition features (MoRFs). The structure–function relationships of UPS components have not been identified completely; therefore, in this study, we have carried out the functional intrinsic disorder and MoRF analysis for potential neurodegenerative disease and anti-cancer targets of this pathway. Our report represents the presence of significant intrinsic disorder and disorder-based binding regions in several UPS proteins, such as extraproteasomal polyubiquitin receptors (UBQLN1 and UBQLN2), proteasome-associated polyubiquitin receptors (ADRM1 and PSMD4), deubiquitinating enzymes (DUBs) (ATXN3 and USP14), and ubiquitinating enzymes (E2 (UBE2R2) and E3 (STUB1) enzyme). We believe this study will have implications for the conformation-specific roles of different regions of these proteins. This will lead to a better understanding of the molecular basis of UPS-associated diseases.

The Cryo-EM Effect: Structural Biology of Neurodegenerative Disease Proteostasis Factors

2021 ◽  
Author(s):  
Benjamin C Creekmore ◽  
Yi-Wei Chang ◽  
Edward B Lee
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Neurodegenerative Disease ◽  
Electron Tomography ◽  
Ubiquitin Proteasome System ◽  
26S Proteasome ◽  
X Ray Crystallography ◽  
New Information ◽  
A Cell ◽  
Regulate Protein

Abstract Neurodegenerative diseases are characterized by the accumulation of misfolded proteins. This protein aggregation suggests that abnormal proteostasis contributes to aging-related neurodegeneration. A better fundamental understanding of proteins that regulate proteostasis may provide insight into the pathophysiology of neurodegenerative disease and may perhaps reveal novel therapeutic opportunities. The 26S proteasome is the key effector of the ubiquitin-proteasome system responsible for degrading polyubiquitinated proteins. However, additional factors, such as valosin-containing protein (VCP/p97/Cdc48) and C9orf72, play a role in regulation and trafficking of substrates through the normal proteostasis systems of a cell. Nonhuman AAA+ ATPases, such as the disaggregase Hsp104, also provide insights into the biochemical processes that regulate protein aggregation. X-ray crystallography and cryo-electron microscopy (cryo-EM) structures not bound to substrate have provided meaningful information about the 26S proteasome, VCP, and Hsp104. However, recent cryo-EM structures bound to substrate have provided new information about the function and mechanism of these proteostasis factors. Cryo-EM and cryo-electron tomography data combined with biochemical data have also increased the understanding of C9orf72 and its role in maintaining proteostasis. These structural insights provide a foundation for understanding proteostasis mechanisms with near-atomic resolution upon which insights can be gleaned regarding the pathophysiology of neurodegenerative diseases.

scholarly journals Biodiversity of echinoids and their epibionts around the Scotia Arc, Antarctica

2008 ◽  
Vol 20 (3) ◽  
pp. 227-244 ◽  
Author(s):  
Katrin Linse ◽  
Lisa J. Walker ◽  
David K.A. Barnes
Keyword(s):  
Southern Ocean ◽  
Current Knowledge ◽  
Sea Urchins ◽  
Marine Biodiversity ◽  
Current View ◽  
Depth Range ◽  
Tissue Mass ◽  
Scotia Arc ◽  
Biodiversity Changes ◽  
Study Species

AbstractThe Scotia Arc, linking the Magellan region with the Antarctic Peninsula, comprises young and old islands both near continents and isolated, and is the only semi-continuous link between cool temperate and Antarctic environments. It is an ideal region for studies on how marine biodiversity changes across an extended transition zone. Echinoids (sea urchins) and their associated epibionts were found across depths from 91–1045 m, with 19 species from shelf and four from slope depths. The 23 species from 38 trawls represent 31% of all echinoid species known from the Southern Ocean and 38% of the shelf/upper slope echinoids. The specimens collected comprise representatives of the five families Cidaridae, Echinidae, Temnopleuridae, Schizasteridae and Pourtalesiidae. Echinoids are probably a good model for how well we know Antarctic shelf and slope megabenthos; none of the species we report are new to science but we found nine (39%) of our study species present at new localities, some thousands of kilometres from previous findings. New biogeographic ranges are illustrated forCtenocidaris gigantea,C. nutrix,C. spinosa,Abatus curvidens,A. ingens,A. shackletoni,Amphineustes rostratus,Tripylaster philippiandPourtalesia aurorae. Southern Ocean echinoids show eurybathy as the mean depth range of our study species was 1241 m and only one was at less than 500 m. The current view of echinoid dominance of super-abundance in the shallows seems to be not transferable to shelf and slope depths as only one of 38 trawls was dominated by echinoids. Current knowledge on maximum sizes in Antarctic echinoids seems to be good as our morphometric measurements were mainly within known size ranges. Regular echinoids increased predictably in mass with increasing test length, apart fromCtenocidaris spinosa. Tissue mass of cidaroid species was ~17%, but across irregular species varied from 17.7–8.9%. No epibionts were found on irregular echinoids or Echinidae but 70 cidaroids examined carried 51 species representing ten classes. Many of these species are reported as cidaroid epibionts for the first time. Cidaroids and their epibionts constituted > 38% of the total macrofaunal richness in the trawls they were present in. Echinoids and their epibionts clearly contribute significantly to Southern Ocean biodiversity but are minor components of biomass except in the shallows.

scholarly journals Accumulation of Mutant Huntingtin Fragments in Aggresome-like Inclusion Bodies as a Result of Insufficient Protein Degradation

2001 ◽  
Vol 12 (5) ◽  
pp. 1393-1407 ◽  
Author(s):  
Stephanie Waelter ◽  
Annett Boeddrich ◽  
Rudi Lurz ◽  
Eberhard Scherzinger ◽  
Gerhild Lueder ◽  
...  
Keyword(s):  
Inclusion Bodies ◽  
Rna Binding ◽  
Ubiquitin Proteasome System ◽  
26S Proteasome ◽  
Therapeutic Interventions ◽  
Ultrastructural Changes ◽  
Huntingtin Protein ◽  
Fibrillar Morphology ◽  
Exon 1 ◽  
Ubiquitin Proteasome

The huntingtin exon 1 proteins with a polyglutamine repeat in the pathological range (51 or 83 glutamines), but not with a polyglutamine tract in the normal range (20 glutamines), form aggresome-like perinuclear inclusions in human 293 Tet-Off cells. These structures contain aggregated, ubiquitinated huntingtin exon 1 protein with a characteristic fibrillar morphology. Inclusion bodies with truncated huntingtin protein are formed at centrosomes and are surrounded by vimentin filaments. Inhibition of proteasome activity resulted in a twofold increase in the amount of ubiquitinated, SDS-resistant aggregates, indicating that inclusion bodies accumulate when the capacity of the ubiquitin–proteasome system to degrade aggregation-prone huntingtin protein is exhausted. Immunofluorescence and electron microscopy with immunogold labeling revealed that the 20S, 19S, and 11S subunits of the 26S proteasome, the molecular chaperones BiP/GRP78, Hsp70, and Hsp40, as well as the RNA-binding protein TIA-1, the potential chaperone 14–3-3, and α-synuclein colocalize with the perinuclear inclusions. In 293 Tet-Off cells, inclusion body formation also resulted in cell toxicity and dramatic ultrastructural changes such as indentations and disruption of the nuclear envelope. Concentration of mitochondria around the inclusions and cytoplasmic vacuolation were also observed. Together these findings support the hypothesis that the ATP-dependent ubiquitin–proteasome system is a potential target for therapeutic interventions in glutamine repeat disorders.

scholarly journals Interaction between Parkin and α-Synuclein in PARK2-Mediated Parkinson’s Disease

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 283
Author(s):  
Daniel Aghaie Madsen ◽  
Sissel Ida Schmidt ◽  
Morten Blaabjerg ◽  
Morten Meyer
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ubiquitin Ligase ◽  
Current Knowledge ◽  
Lewy Bodies ◽  
Ubiquitin Proteasome System ◽  
Loss Of Function ◽  
Functional Interaction ◽  
Future Studies ◽  
Ubiquitin Proteasome

Parkin and α-synuclein are two key proteins involved in the pathophysiology of Parkinson’s disease (PD). Neurotoxic alterations of α-synuclein that lead to the formation of toxic oligomers and fibrils contribute to PD through synaptic dysfunction, mitochondrial impairment, defective endoplasmic reticulum and Golgi function, and nuclear dysfunction. In half of the cases, the recessively inherited early-onset PD is caused by loss of function mutations in the PARK2 gene that encodes the E3-ubiquitin ligase, parkin. Parkin is involved in the clearance of misfolded and aggregated proteins by the ubiquitin-proteasome system and regulates mitophagy and mitochondrial biogenesis. PARK2-related PD is generally thought not to be associated with Lewy body formation although it is a neuropathological hallmark of PD. In this review article, we provide an overview of post-mortem neuropathological examinations of PARK2 patients and present the current knowledge of a functional interaction between parkin and α-synuclein in the regulation of protein aggregates including Lewy bodies. Furthermore, we describe prevailing hypotheses about the formation of intracellular micro-aggregates (synuclein inclusions) that might be more likely than Lewy bodies to occur in PARK2-related PD. This information may inform future studies aiming to unveil primary signaling processes involved in PD and related neurodegenerative disorders.

scholarly journals Ccr4 is a novel shuttle factor required for ubiquitin-dependent proteolysis by the 26S proteasome

2020 ◽  
Author(s):  
Ganapathi Kandasamy ◽  
Ashis Kumar Pradhan ◽  
R Palanimurugan
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Protein Degradation ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Rna Degradation ◽  
26S Proteasome ◽  
Cellular Proteins ◽  
Cellular Homeostasis ◽  
Substrate Degradation ◽  
Ubiquitin Proteasome

AbstractDegradation of short-lived and abnormal proteins are essential for normal cellular homeostasis. In eukaryotes, such unstable cellular proteins are selectively degraded by the ubiquitin proteasome system (UPS). Furthermore, abnormalities in protein degradation by the UPS have been linked to several human diseases. Ccr4 protein is a known component of the Ccr4-Not complex, which has established roles in transcription, mRNA de-adenylation and RNA degradation etc. Excitingly in this study, we show that Ccr4 protein has a novel function as a shuttle factor that promotes ubiquitin-dependent degradation of short-lived proteins by the 26S proteasome. Using a substrate of the well-studied ubiquitin fusion degradation (UFD) pathway, we found that its UPS-mediated degradation was severely impaired upon deletion of CCR4 in Saccharomyces cerevisiae. Additionally, we show that Ccr4 binds to cellular ubiquitin conjugates and the proteasome. In contrast to Ccr4, most other subunits of the Ccr4-Not complex proteins are dispensable for UFD substrate degradation. From our findings we conclude that Ccr4 functions in the UPS as a shuttle factor targeting ubiquitylated substrates for proteasomal degradation.

scholarly journals The Role of epigenetic modifications of DNA and histones in the treatment of oncohematological diseases

2021 ◽  
Vol 66 (2) ◽  
pp. 263-279
Author(s):  
D. V. Karpenko ◽  
N. A. Petinati ◽  
N. J. Drize ◽  
A. E. Bigildeev
Keyword(s):  
Clinical Trial ◽  
Cytosine Methylation ◽  
Current Knowledge ◽  
Hypomethylating Agents ◽  
Epigenetic Change ◽  
Therapeutic Approaches ◽  
Enzymatic Machinery ◽  
Key Pathways ◽  
Dna Cytosine Methylation

Introduction. Current knowledge of tumour biology attests a dual genetic and epigenetic nature of cancer cell abnormalities. Tumour epigenetics research provided insights into the key pathways mediating oncogenesis and facilitated novel epigenetic therapies.Aim — an overview of intricate involvement of epigenetic change in haematological morbidity and current therapeutic approaches to target the related mechanisms.Main findings. We review the best known epigenetic marks in tumour cells, e.g. DNA cytosine methylation, methylation and acetylation of histone proteins, the underlying enzymatic machinery and its role in oncogenesis. The epigenetic profile-changing drugs are described, including DNA hypomethylating agents, histone deacetylase and methylase inhibitors. A particular focus is made on substances currently approved in haematological therapy or undergoing clinical trial phases for future clinical availability.

scholarly journals Ubiquitin carboxyl-terminal hydrolases are required for period maintenance of the circadian clock at high temperature in Arabidopsis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ryosuke Hayama ◽  
Peizhen Yang ◽  
Federico Valverde ◽  
Tsuyoshi Mizoguchi ◽  
Ikuyo Furutani-Hayama ◽  
...  
Keyword(s):  
Circadian Clock ◽  
High Temperatures ◽  
Elevated Temperatures ◽  
Control Period ◽  
Ubiquitin Proteasome System ◽  
26S Proteasome ◽  
Cellular Processes ◽  
Control Functions ◽  
Ubiquitin Proteasome ◽  
Carboxyl Terminal

AbstractProtein ubiquitylation participates in a number of essential cellular processes including signal transduction and transcription, often by initiating the degradation of specific substrates through the 26S proteasome. Within the ubiquitin-proteasome system, deubiquitylating enzymes (DUBs) not only help generate and maintain the supply of free ubiquitin monomers, they also directly control functions and activities of specific target proteins by modulating the pool of ubiquitylated species. Ubiquitin carboxyl-terminal hydrolases (UCHs) belong to an enzymatic subclass of DUBs, and are represented by three members in Arabidopsis, UCH1, UCH2 and UCH3. UCH1 and UCH2 influence auxin-dependent developmental pathways in Arabidopsis through their deubiquitylation activities, whereas biological and enzymatic functions of UCH3 remain unclear. Here, we demonstrate that Arabidopsis UCH3 acts to maintain the period of the circadian clock at high temperatures redundantly with UCH1 and UCH2. Whereas single uch1, uch2 and uch3 mutants have weak circadian phenotypes, the triple uch mutant displays a drastic lengthening of period at high temperatures that is more extreme than the uch1 uch2 double mutant. UCH3 also possesses a broad deubiquitylation activity against a range of substrates that link ubiquitin via peptide and isopeptide linkages. While the protein target(s) of UCH1-3 are not yet known, we propose that these DUBs act on one or more factors that control period length of the circadian clock through removal of their bound ubiquitin moieties, thus ensuring that the clock oscillates with a proper period even at elevated temperatures.

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