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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Modification of cellular proteins with a small protein called ubiquitin has profound effects on their activities. Ubiquitin is covalently attached to lysine residues of acceptor proteins through the concerted action of E1 ubiquitin-activating enzyme, E2 ubiquitin-carrier proteins and E3 ligases. Mammalian cells contain a large number of E3 ligases, which determine the specificity of ubiquitination reactions. Recent studies have revealed that ubiquitination can be reversed by deubiquitinating enzymes that release ubiquitin monomers from modified proteins. Signalling networks that control inflammation are tightly regulated by a multitude of ubiquitination and deubiquitination reactions. This article begins by summarising current understanding of these pathways at a molecular level, and then focuses on the importance of ubiquitination and deubiquitination during the regulation of the pro-inflammatory transcription factor NF-kappaB. Finally, the potential for ubiquitin modifications to be targeted by novel classes of anti-inflammatory drugs is discussed.
Expert Rev Mol Med 2005 Jun 20
PMID:Regulation of pro-inflammatory signalling networks by ubiquitin: identification of novel targets for anti-inflammatory drugs. 1596 57

Ubiquitin-binding domains (UBDs) are a collection of modular protein domains that non-covalently bind to ubiquitin. These recently discovered motifs interpret and transmit information conferred by protein ubiquitylation to control various cellular events. Detailed molecular structures are known for a number of UBDs, but to understand their mechanism of action, we also need to know how binding specificity is determined, how ubiquitin binding is regulated, and the function of UBDs in the context of full-length proteins. Such knowledge will be key to our understanding of how ubiquitin regulates cellular proteins and processes.
Nat Rev Mol Cell Biol 2005 Aug
PMID:Ubiquitin-binding domains. 1606 37

Ubiquitin-containing cellular inclusions are characteristic of major neurodegenerative diseases and suggest an involvement of the ubiquitin-proteasome system. The frameshifted form of ubiquitin has proved to be a valuable tool for studying the role of the ubiquitin-proteasome system. It is an endogenous reporter for proteasome activity in human pathology but it is also capable of inhibiting proteasomal degradation. Current studies have revealed that the frameshifted form of ubiquitin accumulates in the brains of patients with Alzheimer's disease but not in those with Parkinson's disease.
Trends Mol Med 2005 Nov
PMID:The proteasome in Alzheimer's disease and Parkinson's disease: lessons from ubiquitin B+1. 1621 90

Ubiquitin-like domains are present, apart from ubiquitin-like proteins themselves, in many multidomain proteins involved in different signal transduction processes. The sequence conservation for all ubiquitin superfold family members is rather poor, even between subfamily members, leading to mistakes in sequence alignments using conventional sequence alignment methods. However, a correct alignment is essential, especially for in silico methods that predict binding partners on the basis of sequence and structure. In this study, using 3D-structural information we have generated and manually corrected sequence alignments for proteins of the five ubiquitin superfold subfamilies. On the basis of this alignment, we suggest domains for which structural information will be useful to allow homology modelling. In addition, we have analysed the energetic and electrostatic properties of ubiquitin-like domains in complex with various functional binding proteins using the protein design algorithm FoldX. On the basis of an in silico alanine-scanning mutagenesis, we provide a detailed binding epitope mapping of the hotspots of the ubiquitin domain fold, involved in the interaction with different domains and proteins. Finally, we provide a consensus fingerprint sequence that identifies all sequences described to belong to the ubiquitin superfold family. It is possible that the method that we describe may be applied to other domain families sharing a similar fold but having low levels of sequence homology.
J Mol Biol 2006 Jan 27
PMID:The ubiquitin domain superfold: structure-based sequence alignments and characterization of binding epitopes. 1631 Feb 15

Ubiquitin conjugation typically requires three classes of enzyme: E1, E2, and E3. A fourth type of enzyme (E4), however, was recently shown to be required for the degradation of certain types of substrate in yeast. We previously identified UFD2a (also known as E4B) as an E4 in mammals. UFD2a is exclusively expressed in cardiac muscle during mouse embryonic development, but it is abundant in neurons of adult mice and is implicated in the pathogenesis of neurodegenerative disease. The precise physiological function of this enzyme has remained largely unknown, however. Here, we show that mice lacking UFD2a die in utero, manifesting marked apoptosis in the developing heart. Polyubiquitylation activity for an E4 substrate was greatly reduced in Ufd2a(-/-) mouse embryonic fibroblasts. Furthermore, Ufd2a(+/-) mice displayed axonal dystrophy in the nucleus gracilis, as well as degeneration of Purkinje cells accompanied by endoplasmic reticulum stress. These animals also developed a neurological disorder. UFD2a thus appears to be essential for the development of cardiac muscle, as well as for the protection of spinocerebellar neurons from degeneration induced by endoplasmic reticulum stress.
Mol Cell Biol 2005 Dec
PMID:Mammalian E4 is required for cardiac development and maintenance of the nervous system. 1631 18

Ubiquitin and other ubiquitin-like proteins play important roles in post-translational modification. They are phylogenetically well-conserved in eukaryotes. Activated by other proteins, ubiquitin and ubiquitin-like proteins can covalently modify target proteins. The enzymes responsible for the activation of this modification have been known to include UBA1, SAE2, UBA3, SAE1 and ULA1. Here we report a new ubiquitin activating enzyme like cDNA, named ubiquitin activating enzyme E1-domain containing 1 (UBE1DC1), whose cDNA is 2654 base pairs in length and contains an open reading frame encoding 404 amino acids. The UBE1DC1 gene consists of 12 exons and is located at human chromosome 3q22. The result of RT-PCR showed that UBE1DC1 is expressed in most of human tissues.
Mol Biol Rep 2005 Dec
PMID:Isolation and characterization of ubiquitin-activating enzyme E1-domain containing 1, UBE1DC1. 1632 88

Ubiquitin specific proteases (USPs) regulate the production and recycling of ubiquitin and are thereby critically involved in the control of cell growth, differentiation, and apoptosis. Increasing evidence implicates deregulation of USPs in malignant transformation but there is very little information on the overall and specific activity of USPs in normal and tumor tissues. We have used a chemistry-based functional proteomics approach to profile the activities of individual USPs in biopsies of human papillomavirus (HPV) carrying cervical carcinoma and adjacent normal tissue. To assess the contribution of HPV proteins, USP activity was also compared in HPV positive and negative cervical carcinoma cell lines and HPV E6/E7 immortalized human keratinocytes. The activity of the C-terminal hydrolases UCH-L3 and UCH37 was upregulated in the majority of tumor tissues compared to the adjacent normal tissues. UCH-L1 activity was lower in a significant proportion of the tumors but to a less extent in advanced tumors. In accordance with the relatively low UCH-L1 activity in tumor biopsies, UCH-L1 was detected only in one out of eight cervical carcinoma lines. UCH-L1, UCH-L3, USP7, and USP9X activity was upregulated following HPV E6/E7 immortalization of keratinocytes, suggesting a role of these enzymes in growth transformation.
Mol Carcinog 2006 Apr
PMID:Activity profiling of deubiquitinating enzymes in cervical carcinoma biopsies and cell lines. 1640 89

Ubiquitin-mediated proteolysis plays a key role in many pathways inside the cell and is particularly important in regulating cell cycle transitions. SCF (Skp1/Cul1/F-box protein) complexes are modular ubiquitin ligases whose specificity is determined by a substrate-binding F-box protein. Dia2 is a Saccharomyces cerevisiae F-box protein previously described to play a role in invasive growth and pheromone response pathways. We find that deletion of DIA2 renders cells cold-sensitive and subject to defects in cell cycle progression, including premature S-phase entry. Consistent with a role in regulating DNA replication, the Dia2 protein binds replication origins. Furthermore, the dia2 mutant accumulates DNA damage in both S and G2/M phases of the cell cycle. These defects are likely a result of the absence of SCF(Dia2) activity, as a Dia2 DeltaF-box mutant shows similar phenotypes. Interestingly, prolonging G1-phase in dia2 cells prevents the accumulation of DNA damage in S-phase. We propose that Dia2 is an origin-binding protein that plays a role in regulating DNA replication.
Mol Biol Cell 2006 Apr
PMID:The F-box protein Dia2 regulates DNA replication. 1642 Dec 50

Ubiquitin-dependent protein degradation usually involves escort factors that target ubiquitylated substrates to the proteasome. A central element in a major escort pathway is Cdc48, a chaperone-like AAA ATPase that collects ubiquitylated substrates via alternative substrate-recruiting cofactors. Cdc48 also associates with Ufd2, an E4 multiubiquitylation enzyme that adds further ubiquitin moieties to preformed ubiquitin conjugates to promote degradation. Here, we show that E4 can be counteracted in vivo by two distinct mechanisms. First, Ufd3, a WD40 repeat protein, directly competes with Ufd2, because both factors utilize the same docking site on Cdc48. Second, Cdc48 also binds Otu1, a deubiquitylation enzyme, which disassembles multiubiquitin chains. Notably, Cdc48 can bind Otu1 and Ufd3 simultaneously, making a cooperation of both inhibitory mechanisms possible. We propose that the balance between the distinct substrate-processing cofactors may determine whether a substrate is multiubiquitylated and routed to the proteasome for degradation or deubiquitylated and/or released for other purposes.
Mol Cell 2006 Jan 20
PMID:Functional division of substrate processing cofactors of the ubiquitin-selective Cdc48 chaperone. 1642 15

Ras proteins are essential components of signal transduction pathways that control cell proliferation, differentiation, and survival. It is well recognized that the functional versatility of Ras proteins is accomplished through their differential compartmentalization, but the mechanisms that control their spatial segregation are not fully understood. Here we show that HRas is subject to ubiquitin conjugation, whereas KRas is refractory to this modification. The membrane-anchoring domain of HRas is necessary and sufficient to direct the mono- and diubiquitination of HRas. Ubiquitin attachment to HRas stabilizes its association with endosomes and modulates its ability to activate the Raf/MAPK signaling pathway. Therefore, differential ubiquitination of Ras proteins may control their location-specific signaling activities.
Mol Cell 2006 Mar 03
PMID:Differential modification of Ras proteins by ubiquitination. 1650 65


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