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213 results for “proteasome”
Molecular Details Underlying Dynamic Structures and Regulation of the Human 26S Proteasome
<p>The 26S proteasome is the macromolecular machine responsible for ATP/ubiquitin dependent degradation. As aberration in proteasomal degradation has been implicated in many human diseases, structural analysis of the human 26S proteasome complex is essential to advance our understanding of its action and regulation mechanisms. In recent years, cross-linking mass spectrometry (XL-MS) has emerged as a powerful tool for elucidating structural topologies of large protein assemblies, with its unique capability of studying protein complexes in cells. To facilitate the identification of cross-linked peptides, we have previously developed a robust amine reactive sulfoxide-containing MS-cleavable cross-linker, disuccinimidyl sulfoxide (DSSO). To better understand the structure and regulation of the human 26S proteasome, we have established new DSSO-based in vivo and in vitro XL-MS workflows by coupling with HB-tag based affinity purification to comprehensively examine protein-protein interactions within the 26S proteasome. In total, we have identified 447 unique lysine-to-lysine linkages delineating 67 inter-protein and 26 intra-protein interactions, representing the largest cross-link dataset for proteasome complexes. In combination with EM maps and computational modeling, the architecture of the 26S proteasome was determined to infer its structural dynamics. In particular, three proteasome subunits Rpn1, Rpn6 and Rpt6 displayed multiple conformations that have not been previously reported. Additionally, cross-links between proteasome subunits and 15 proteasome interacting proteins including 9 known and 6 novel ones have been determined to demonstrate their physical interactions at the amino-acid level. Our results have provided new insights on the dynamics of the 26S human proteasome and the methodologies presented here can be applied to study other protein complexes.</p> <p>For more information about how to reproduce this modeling, see https://salilab.org/26S-PIPs or the README file.</p>
Multi-omic analysis of the Arabidopsis clock activator mutant rve 4 6 8 reveals connections to carbohydrate metabolism and proteasome regulation
<p>Plants are able to sense changes in their light environments, such as the onset of day and night, as well as anticipate these changes in order to adapt and survive. Central to this ability is the plant circadian clock, a molecular circuit that precisely orchestrates plant cell processes over the course of a day. REVEILLE proteins (RVEs) are recently discovered members of the plant circadian circuitry that activate the evening complex and PRR genes to maintain regular circadian oscillation. The RVE 8 protein and its two homologs, RVE 4 and 6, have been shown to limit the length of the circadian period, with rve 4 6 8 triple-knockout plants possessing an elongated period along with increased leaf surface area, biomass, cell size and delayed flowering relative to wild-type Col-0 plants. Here, using a multi-omics approach consisting of phenomics, transcriptomics, proteomics, and metabolomics we draw novel connections between RVE8-like proteins and a number of core plant cell processes. In particular, we reveal that loss of RVE8-like proteins results in altered carbohydrate, organic acid and lipid metabolism, including a starch excess phenotype at dawn. We further demonstrate that rve 4 6 8 plants have lower levels of 20S proteasome subunits and possess significantly reduced proteasome activity, potentially explaining the increase in cell-size observed in RVE8-like mutants. Overall, this robust, multi-omic dataset, provides substantial new insights into the far reaching impact RVE8-like proteins have on the diel plant cell environment.<br> <br> This dataset has the raw search outputs for the mass-spec analysis for this manuscript. </p>
The proteasome-interacting Ecm29 protein disassembles the 26S proteasome in response to oxidative stress
<p>This repository contains the modeling files and the analysis related to the article <a href="https://www.ncbi.nlm.nih.gov/pubmed/28821611">"The proteasome-interacting Ecm29 protein disassembles the 26S proteasome in response to oxidative stress"</a> by Wang et al. in J Biol Chem 2017.</p> <p><strong>For more information</strong> about how to reproduce this modeling, see the <a href="https://salilab.org/ecm29/">Sali lab website</a> or the README file.</p>
Conformational maps of human 20S proteasomes reveal PA28- and immuno-dependant inter-ring crosstalks
<p>Data and R scripts associated to the HDX-MS analysis of the 20S core particule and its PA28 regulators:</p> <p>Here, we used for the first time Hydrogen-Deuterium eXchange coupled to Mass Spectrometry (HDX-MS) to investigate conformational differences between the human standard 20S (std20S) and immuno 20S (i20s) proteasomes alone or in complex with PA28αβ or PA28γ activators. Their solvent accessibility (in the form of deuteration kinetics) were analysed through a dedicated bioinformatic pipeline including stringent statistical analysis and 3D visualisation. These data confirmed the existence of allosteric differences between the std20S and i20S at the surface of the α-ring triggered from inside the catalytic β-ring. Additionally, binding of the PA28 regulators to the 20S proteasomes modified solvent accessibility due to conformational changes of the β-rings. This work is not only a proof of concept that HDX-MS can be used to get structural insights on large multi-protein complexes in solution, it also demonstrates that the binding of the std20S or i20S subtype to any of its PA28 activator triggers allosteric changes that are specific to this 20S/PA28 pair, in terms of the regions affected. </p>
Data from: Evaluating single-cell variability in proteasomal decay
<p>Gene expression is a stochastic process that leads to variability in mRNA and protein abundances even within an isogenic population of cells grown in the same environment. <br>This variation, often called gene-expression noise, has typically been attributed to transcriptional and translational processes while ignoring the contributions of protein decay variability across cells. <br>Here we estimate the single-cell protein decay rates of two degron GFPs in \textit{Saccharomyces cerevisiae} using time-lapse microscopy. <br>We find substantial cell-to-cell variability in the decay rates of the degron GFPs.<br>We evaluate cellular features that explain the variability in the proteasomal decay and find that the amount of 20s catalytic beta subunit of the proteasome marginally explains the observed variability in the degron GFP half-lives. <br>We propose alternate hypotheses that might explain the observed variability in the decay of the two degron GFPs.<br>Overall, our study highlights the importance of studying the kinetics of the decay process at single-cell resolution and that decay rates vary at the single-cell level, and that the decay process is stochastic. <br>A complex model of decay dynamics must be included when modeling stochastic gene expression to estimate gene expression noise.</p>
Cystargolide-based amide and ester Pz analogs as proteasome inhibitors and anticancer agents
<p>A series of cystargolide-based beta-lactone analogs containing nitrogen atoms at the Pz portion of the scaffold were prepared and evaluated as proteasome inhibitors and for their cytotoxicity profile towards several cancer cell lines. Inclusion of one, two or even three nitrogen atoms at the Pz portion of the cystargolide scaffold is well-tolerated, producing analogs with low nanomolar proteasome inhibition activity, in many cases superior to carfilzomib. Additionally, analog 8g, containing an ester and pyrazine group at Pz, was shown to possess significant activity towards RPMI 8226 cells (IC50 = 21 nM) and to be less cytotoxic towards the normal tissue model MCF10A cells than carfilzomib.</p>
A Targeted Phase I/II Trial of ZD6474 (Vandetanib; ZACTIMA) Plus the Proteasome Inhibitor, Bortezomib (Velcade ), in Adults With Solid Tumors With a Focus on Hereditary or Sporadic, Locally Advanced o
ClinicalTrials.gov study NCT00923247. IPD Sharing: NO. Countries: 1. Publications: 4.
Study Augmenting TAK-659 Action in Relapsed/Refractory AML by Addition Ofthe Proteasome Inhibitor Ixazomib
ClinicalTrials.gov study NCT04079738. IPD Sharing: NO. Countries: 1. Publications: 0.
An Efficacy and Safety Study of Daratumumab in Patients With Multiple Myeloma Who Have Received at Least 3 Prior Lines of Therapy (Including a Proteasome Inhibitor [PI] and Immunomodulatory Drug [IMiD
ClinicalTrials.gov study NCT01985126. IPD Sharing: Not stated. Countries: 3. Publications: 6.
Data from: Evaluating single-cell variability in proteasomal decay
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Cystargolide-based amide and ester Pz analogs as proteasome inhibitors and anticancer agents
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Data for: A systems genetics approach identifies roles for proteasome factors in heart development and congenital heart defects
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Single molecule images for: An empirical energy landscape reveals mechanism of proteasome in polypeptide translocation
<p>The ring-like ATPase complexes in the AAA+ family perform diverse cellular functions that require coordination between the conformational transitions of their individual ATPase subunits. How the energy from ATP hydrolysis is captured to perform mechanical work by these coordinated movements is not known. In this study, we developed a novel approach for delineating the nucleotide-dependent free-energy landscape (FEL) of the proteasome's heterohexameric ATPase complex based on complementary structural and kinetic measurements. We used the FEL to simulate the dynamics of the proteasome and quantitatively evaluated the predicted structural and kinetic properties. The FEL model predictions were widely consistent with experimental observations in this and previous studies and suggested novel features of the mechanism of proteasomal ATPase. We find that the cooperative movements of the ATPase subunits result from the design of the ATPase hexamer entailing a unique free-energy minimum for each nucleotide-binding state. ATP hydrolysis dictates the direction of substrate translocation by triggering an energy-dissipating conformational transition of the ATPase complex.</p>
The midnolin-proteasome pathway catches proteins for ubiquitination-independent degradation
<p class="MsoNormal">Cells use ubiquitin to mark proteins for proteasomal degradation. While the proteasome also eliminates proteins that are not modified by ubiquitin, how this occurs mechanistically is unclear. We show here that midnolin promotes the destruction of many nuclear proteins including transcription factors encoded by the immediate-early-genes. Diverse environmental cues induce midnolin and its overexpression is sufficient to cause the degradation of its targets by a mechanism, which, remarkably, does not require ubiquitination. Instead, midnolin associates with the proteasome via <span>an alpha</span><span>-helix</span>, employs its Catch-domain to bind a region within substrates that adopts a beta-strand conformation, and uses a ubiquitin-like-domain to promote substrate destruction. Thus, midnolin contains three regions that function in concert to target a large set of nuclear proteins to the proteasome for degradation. </p>
A Study of Real-life Current Standards of Care in Patients With Relapsed and/or Refractory Multiple Myeloma Who Received at Least 3 Prior Lines of Therapy Including Proteasome Inhibitor (PI), Immunomo
ClinicalTrials.gov study NCT04035226. IPD Sharing: NO. Countries: 10. Publications: 7.
Evaluation of Proteasome as a Marker of Hepatocellular Carcinoma in Cirrhotic Patients Following Curative Treatment
ClinicalTrials.gov study NCT01492127. IPD Sharing: Not stated. Countries: 1. Publications: 1.
Clinical Trial Using Humanized CART Directed Against BCMA (ARI0002h) in Patients With Relapsed/Refractory Multiple Myeloma to Proteasome Inhibitors, Immunomodulators and Anti-CD38 Antibody.
ClinicalTrials.gov study NCT04309981. IPD Sharing: NO. Countries: 1. Publications: 3.
Proteasomal Inhibition for Patients With Mis-sense Mutated Dysferlin
ClinicalTrials.gov study NCT01863004. IPD Sharing: Not stated. Countries: 1. Publications: 3.
Proteasome Inhibitor PS-341 Relapsed or Refractory B Cell Lymphomas Previously Treated With Chemotherapy
ClinicalTrials.gov study NCT00038571. IPD Sharing: Not stated. Countries: 1. Publications: 1.
Prospective Observation of Cardiac Safety With Proteasome Inhibition
ClinicalTrials.gov study NCT02178579. IPD Sharing: NO. Countries: 1. Publications: 1.
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Allen Brain Atlas
Allen Brain Atlas is an Allen Institute collection of brain map atlases, datasets, APIs, and analysis tools covering mouse, human, and non-human primate brain resources.
Annotated Behaviour and Observability Dataset (ABODe)
ABODe is a University of Edinburgh DataShare dataset for behavior classification in group-housed mice using home-cage video, identities, bounding boxes, ground-plate positions, and annotator labels.
DANDI Archive for NWB datasets
DANDI is a BRAIN Initiative archive for publishing and sharing neurophysiology data, including electrophysiology, optophysiology, and behavioral data packaged as NWB and related standards.
International Brain Laboratory public data
The International Brain Laboratory public data releases expose standardized mouse decision-making experiments, including Neuropixels recordings, widefield calcium imaging, behavior, and session metadata accessed through the ONE API.
OpenNeuro
OpenNeuro is a free, open platform for sharing neuroimaging datasets, with public search, dataset pages, and download paths for web, S3, DataLad, and the OpenNeuro CLI.