Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ubiquitin is a ubiquitously expressed 76 amino acid protein that can be covalently attached to target proteins, leading to their ubiquitination. Many ubiquitinated proteins are degraded by the proteasome, a 2000 kDa ATP-dependent proteolytic complex. Numerous studies have demonstrated that the ubiquitination and proteasome system plays an important role in controlling the levels of various cellular proteins and therefore regulates basic cellular processes such as cell cycle progression, signal transduction, and cell transformation. Ubiquitination also directly affects the function and location of target proteins. Recent studies found that ubiquitination-mediated degradation and change in activity regulate many molecules of the cell death machinery, such as p53, caspases, and Bcl-2 family members. Ring finger-containing members of the IAP (inhibitor of apoptosis) family proteins themselves can function as ubiquitin protein ligases to ubiquitinate their target proteins or promote autoubiquitination. It has been demonstrated that degradation of the IAP proteins is required for apoptosis to occur in some systems, indicating apoptosis proceeds by activating death pathways as well as eliminating "roadblocks" through ubiquitination. These new findings also suggest that ubiquitination is one of the major mechanisms that regulate apoptotic cell death and could be a unique target for therapeutic intervention.
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PMID:Regulation of apoptosis: the ubiquitous way. 1272 36

Polyubiquitination is required for retrotranslocation of proteins from the endoplasmic reticulum back into the cytosol, where they are degraded by the proteasome. We have tested whether the release of a polypeptide chain into the cytosol is caused by a ratcheting mechanism in which the attachment of polyubiquitin prevents the chain from moving back into the endoplasmic reticulum. Using a permeabilized cell system in which major histocompatibility complex class I heavy chains are retrotranslocated under the influence of the human cytomegalovirus protein US11, we demonstrate that polyubiquitination alone is insufficient to provide the driving force for retrotranslocation. Substrate release into the cytosol requires an additional ATP-dependent step. Release requires a lysine 48 linkage of ubiquitin chains. It does not occur when polyubiquitination of the substrate is carried out with glutathione S-transferase (GST)-ubiquitin, and this correlates with poly-GST-ubiquitin not being recognized by a ubiquitin-binding domain in the Ufd1-Npl4 cofactor of the ATPase p97. These data suggest that polyubiquitin does not serve as a ratcheting molecule. Rather, it may serve as a recognition signal for the p97-Ufd1-Npl4 complex, a component implicated in the movement of substrate into the cytosol.
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PMID:Polyubiquitin serves as a recognition signal, rather than a ratcheting molecule, during retrotranslocation of proteins across the endoplasmic reticulum membrane. 1281 30

A member of the family of ATPases associated with diverse cellular activities, called p97 in mammals and Cdc48 in yeast, associates with the cofactor Ufd1-Npl4 to move polyubiquitinated polypeptides from the endoplasmic reticulum (ER) membrane into the cytosol for their subsequent degradation by the proteasome. Here, we have studied the mechanism by which the p97-Ufd1-Npl4 complex functions in this retrotranslocation pathway. Substrate binding occurs when the first ATPase domain of p97 (D1 domain) is in its nucleotide-bound state, an interaction that also requires an association of p97 with the membrane through its NH2-terminal domain. The two ATPase domains (D1 and D2) of p97 appear to alternate in ATP hydrolysis, which is essential for the movement of polypeptides from the ER membrane into the cytosol. The ATPase itself can interact with nonmodified polypeptide substrates as they emerge from the ER membrane. Polyubiquitin chains linked by lysine 48 are recognized in a synergistic manner by both p97 and an evolutionarily conserved ubiquitin-binding site at the NH2 terminus of Ufd1. We propose a dual recognition model in which the ATPase complex binds both a nonmodified segment of the substrate and the attached polyubiquitin chain; polyubiquitin binding may activate the ATPase p97 to pull the polypeptide substrate out of the membrane.
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PMID:Function of the p97-Ufd1-Npl4 complex in retrotranslocation from the ER to the cytosol: dual recognition of nonubiquitinated polypeptide segments and polyubiquitin chains. 1284 84

Insulin-degrading enzyme (IDE) is a metalloprotease implicated in insulin degradation and suggested to have a variety of additional functions, including the clearance of amyloid beta peptides of Alzheimer's disease. Little is known about endogenous proteins that may interact with and modulate IDE's activity in the cell. We purified and characterized two proteins from mouse leukemic splenocytes that interact with IDE and inhibit its insulin-degrading activity. A protein of 14 kDa was similar to a competitive IDE inhibitor reported previously. The major inhibitor was identified by amino acid sequencing as ubiquitin, a protein that is post-translationally covalently attached to other intracellular proteins and regulates diverse cellular processes. Ubiquitin inhibited insulin-degrading activity of IDE and diminished crosslinking of 125I-insulin to IDE in a specific, concentration-dependent, reversible, and ATP-independent manner. Ubiquitin did not affect the crosslinking of 125I-insulin to insulin receptors or of 125I-atrial natriuretic peptide (ANP) to its receptor guanylate cyclase-A. These findings suggest a novel role for ubiquitin or perhaps proteins with ubiquitin-like domains in regulating the function of IDE.
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PMID:Non-covalent interaction of ubiquitin with insulin-degrading enzyme. 1285 Feb 77

HSP27 is an ATP-independent chaperone that confers protection against apoptosis through various mechanisms, including a direct interaction with cytochrome c. Here we show that HSP27 overexpression in various cell types enhances the degradation of ubiquitinated proteins by the 26S proteasome in response to stressful stimuli, such as etoposide or tumor necrosis factor alpha (TNF-alpha). We demonstrate that HSP27 binds to polyubiquitin chains and to the 26S proteasome in vitro and in vivo. The ubiquitin-proteasome pathway is involved in the activation of transcription factor NF-kappaB by degrading its main inhibitor, I-kappaBalpha. HSP27 overexpression increases NF-kappaB nuclear relocalization, DNA binding, and transcriptional activity induced by etoposide, TNF-alpha, and interleukin 1beta. HSP27 does not affect I-kappaBalpha phosphorylation but enhances the degradation of phosphorylated I-kappaBalpha by the proteasome. The interaction of HSP27 with the 26S proteasome is required to activate the proteasome and the degradation of phosphorylated I-kappaBalpha. A protein complex that includes HSP27, phosphorylated I-kappaBalpha, and the 26S proteasome is formed. Based on these observations, we propose that HSP27, under stress conditions, favors the degradation of ubiquitinated proteins, such as phosphorylated I-kappaBalpha. This novel function of HSP27 would account for its antiapoptotic properties through the enhancement of NF-kappaB activity.
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PMID:HSP27 is a ubiquitin-binding protein involved in I-kappaBalpha proteasomal degradation. 1289 49

The ubiquitin-proteasome pathway plays a role in the degradation of the bulk of proteins in the cytoplasmic and nuclear compartments. In this pathway proteins are targeted for degradation by covalent ligation with ubiquitin, a reaction that requires ATP. Following the binding of the first ubiquitin molecule with the epsilon-amino group of a lysine residue of the substrate protein, a polyubiquitin chain is usually formed, in which the C-terminus of each ubiquitin unit is linked to a specific Lys residue of the previous ubiquitin. Central to this pathway is the 26S proteasome, a high molecular mass multifunctional protease which requires ATP for its catalytic activity. Substrates of the 26S proteasome are not only old or damaged proteins, but also short lived proteins functioning as regulatory factors in a large array of cellular processes, such as cell cycle progression, cell growth and gene expression, inflammatory response and immune surveillance. A number of inhibitors of the catalytic activity of proteasomes have been developed and successfully employed in the study of their functional and structural properties, as well as of their involvement in different cellular processes. Some of these molecules due to their toxicity are used only as experimental research tools; others instead are now in clinical trials for treatment of a variety of hematologic malignancies and solid tumors and of reperfusion injury occurring after cerebral ischemia and myocardial infarction. Furthermore, proteasome inhibitors are described to interfere with HIV maturation, budding and aggressiveness, and cytostatic drugs, as well as antiretroviral agents used in HAART, have been shown to behave in vitro and in cultured cell lines as inhibitors of proteasome proteolytic activity at therapeutic dosages.
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PMID:Proteasomes as drug targets. 1457 57

Ubiquitin and ubiquitin-like modifiers (UBLs) form covalent complexes with other proteins by isopeptide formation between their carboxyl (C)-termini and epsilon-amino groups of lysine residues of acceptor proteins. A hallmark of UBLs is a protruding C-terminal tail with a terminal glycine residue, which is required for ATP-dependent conjugation. Recently, the highly conserved protein HUB1 (homologous to ubiquitin 1) has been reported to function as a UBL following C-terminal processing. HUB1 exhibits sequence similarity with ubiquitin but lacks a C-terminal tail bearing a glycine residue. Here we show that HUB1 can form SDS-resistant complexes with cellular proteins, but provide evidence that these adducts are not formed through covalent C-terminal conjugation of HUB1 to substrates. The adducts are still formed when the C-terminus of HUB1 was altered by epitope tagging, amino-acid exchange or deletion, or when cells were depleted of ATP. We propose that HUB1 may act as a novel protein modulator through the formation of tight, possibly noncovalent interactions with target proteins.
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PMID:The ubiquitin-like protein HUB1 forms SDS-resistant complexes with cellular proteins in the absence of ATP. 1460 71

The 26 S proteasome is a multisubunit protease complex responsible for degrading a wide range of intracellular proteins in eukaryotes, especially those modified with polyubiquitin chains. It is composed of a self-compartmentalized core protease (CP) that houses the peptidase active sites appended on either or both ends by a regulatory particle (RP) that identifies appropriate substrates and translocates them into the lumen of the CP for breakdown. Here, we describe the molecular and biochemical properties of the 26 S proteasome from the plant Arabidopsis thaliana. Like the CP and the ATPase ring of the RP, the RP non-ATPase subunits are often encoded by two transcriptionally active genes with some pairs displaying sufficient sequence divergence to suggest functional differences. Most RPN subunits could functionally replace their yeast counterparts, implying that they have retained their positions and activities within the complex. A method was developed to purify the 26 S proteasome intact from whole Arabidopsis seedlings. These preparations are biochemically indistinguishable from those from yeast and mammals, including the need for ATP to maintain integrity and a strong sensitivity to the inhibitors MG115, MG132, lactacystin, and epoxomicin. Mass spectrometric analysis of the complex detected the presence of almost all CP and RP subunits. In many cases, both products of paralogous genes were detected, demonstrating that each isoform assembles into the mature particle. As with the yeast and animal 26 S proteasomes, attenuation of individual RP genes induces a coordinated up-regulation of many of the other 26 S proteasome genes, suggesting that plants contain a negative feedback mechanism to regulate the 26 S proteasome levels. The incorporation of paralogous subunits into the Arabidopsis holoprotease raises the intriguing possibility that plants synthesize multiple 26 S proteasome types with unique properties and/or target specificities.
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PMID:Purification of the Arabidopsis 26 S proteasome: biochemical and molecular analyses revealed the presence of multiple isoforms. 1462 84

Endogenous opioids have been implicated in the pathway of tolerance to stresses. Hibernating tissues tolerate stress. Serum from hibernating woodchucks (hibernation induction trigger [HIT]), from summer nonhibernating animals (summer woodchuck active plasma [SWAP], and potential "hibernation opioid mimics" (D-Ala(2) D Leu(5) Enkephalin [DADLE]), and Deltorphin D (Delt D) were used as ischemic preconditioning agents (IPC) in an in vivo surgically induced cardiac ischemia rat model. Comparison of the IPC treatment was monitored by the molecular intensity of stress transcripts for polyubiquitin and HSP70 in Northern blot analyses. Delt D and HIT significantly reduced total polyubiquitin transcript expression, 2.1-fold and 1.4-fold, respectively, in ischemic tissue, while SWAP and DADLE did not differ from saline controls. The Delt D effect was sensitive to glibenclamide (Glb), a K(ATP) (potassium adenosine triphosphate) channel blocker. No inducible HSP70 was detected. The demonstration of an opioid IPC modulation of the ubiquitin stress pathway found here may be relevant for development of drug intervention in heart attacks and stroke.
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PMID:Alternative strategy for stress tolerance: opioids. 1512 52

The proteasome is the main ATP-dependent protease in eukaryotic cells and controls the concentration of many regulatory proteins in the cytosol and nucleus. Proteins are targeted to the proteasome by the covalent attachment of polyubiquitin chains. The ubiquitin modification serves as the proteasome recognition element but by itself is not sufficient for efficient degradation of folded proteins. We report that proteolysis of tightly folded proteins is accelerated greatly when an unstructured region is attached to the substrate. The unstructured region serves as the initiation site for degradation and is hydrolyzed first, after which the rest of the protein is digested sequentially. These results identify the initiation site as a novel component of the targeting signal, which is required to engage the proteasome unfolding machinery efficiently. The proteasome degrades a substrate by first binding to its ubiquitin modification and then initiating unfolding at an unstructured region.
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PMID:An unstructured initiation site is required for efficient proteasome-mediated degradation. 1533 74


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