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Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ubiquitin and ubiquitin-like proteins are conjugated to a wide variety of target proteins that play roles in all biological processes. Target proteins are conjugated to ubiquitin monomers or to ubiquitin polymers that form via all seven internal lysine residues of ubiquitin. The fate of these target proteins is controlled in a chain architecture-dependent manner. SUMO (small ubiquitin-related modifier) shares the ability of ubiquitin to form chains via internal SUMOylation sites. Interestingly, a SUMO-binding site in Ubc9 is important for SUMO chain synthesis. Similar to ubiquitin-polymer cleavage by USPs (ubiquitin-specific proteases), SUMO chain formation is reversible. SUMO polymers are cleaved by the SUMO proteases SENP6 [SUMO/sentrin/SMT3 (suppressor of mif two 3)-specific peptidase 6], SENP7 and Ulp2 (ubiquitin-like protease 2). SUMO chain-binding proteins including ZIP1, SLX5/8 (synthetic lethal of unknown function 5/8), RNF4 (RING finger protein 4) and CENP-E (centromere-associated protein E) have been identified that interact non-covalently with SUMO chains, thereby regulating target proteins that are conjugated to SUMO multimers. SUMO chains play roles in replication, in the turnover of SUMO targets by the proteasome and during mitosis and meiosis. Thus signalling via polymers is an exciting feature of the SUMO family.
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PMID:SUMO chains: polymeric signals. 2007 33

It has been more than 30 years since the initial report of the discovery of ubiquitin as an 8.5 kDa protein of unknown function expressed universally in living cells. And still, protein modification by covalent conjugation of the ubiquitin molecule is one of the most dynamic posttranslational modifications studied in terms of biochemistry and cell physiology. Ubiquitination plays a central regulatory role in number of eukaryotic cellular processes such as receptor endocytosis, growth-factor signaling, cell-cycle control, transcription, DNA repair, gene silencing, and stress response. Ubiquitin conjugation is a three step concerted action of the E1-E2-E3 enzymes that produces a modified protein. In this review we investigate studies undertaken to identify both ubiquitin and SUMO (small ubiquitin-related modifier) substrates with the goal of understanding how lysine selectivity is achieved. The SUMOylation pathway though distinct from that of ubiquitination, draws many parallels. Based upon the recent findings, we present a model to explain how an individual ubiquitin ligase may target specific lysine residue(s) with the co-operation from a scaffold protein.
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PMID:Defining an Embedded Code for Protein Ubiquitination. 2014 94

The fifth international conference on SUMO, Ubiquitin, UBL Proteins: Implications for Human Diseases, held in Houston, included topics covering the latest advances and new targets in the field of protein modification. This conference report highlights selected presentations on the structural characterization of ubiquitination and SUMOylation machinery; the regulation of ubiquitination enzymes, including E3 ligases; the functions and mechanism of action of SUMO-targeted ubiquitin ligases (STUbLs); the regulation of gene expression by SUMO; non-degradative functions of ubiquitin and SUMO in signal transduction; mechanisms and functions of ISG15 conjugation; the interaction of pathogens with host cell SUMOylation machinery; and stabilization of the Axin protein. Investigational drugs discussed include MLN-4924 (Millennium Pharmaceuticals Inc).
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PMID:SUMO, Ubiquitin, UBL Proteins: Implications For Human Diseases - Fifth International Conference. 2037 48

The rise of proteomics has had tremendous influence on analysis and understanding of the role of post-translational modifications in biological processes. The covalent attachment of small proteins like ubiquitin, SUMO,(1) or other ubiquitin-like proteins (Ubls) is one class of post-translational modifications where proteomics has had notable impact. Various proteomics approaches, but in particular mass spectrometry-based analyses, have influenced the field and enabled significant advances over the past few years. The first meeting dedicated to proteomics of protein degradation and ubiquitin pathways showcased these advances and allowed a glimpse at future contributions of proteomics to this field. With its many attractive drug targets, the ubiquitin and proteasome system, as well as other proteolysis pathways, could offer new therapies for various human diseases including cancer and neurodegenerative disorders. The covalent linkage of ubiquitin to other proteins is catalyzed by the E1-E2-E3 cascade of enzymatic reactions whereby the many different E3 ubiquitin ligases provide substrate specificity to the process of protein ubiquitylation (1). Ubiquitylation is best known for targeting proteins for degradation by the proteasome, but other functions for ubiquitylation independent of proteolysis are also known. Likewise, modifications with SUMO or other Ubls generally do not regulate protein degradation but instead control subcellular localization, protein interactions, or change protein conformation and activity (2). The questions addressed by proteomics approaches to ubiquitylation and Ubl modifications are plentiful. They range from very specific, e.g. determination of the modified residue in a substrate protein, to complex, such as protein dynamics in proteome-wide ubiquitin (or Ubl) modification profiles (3). In either case, the rapid technological advancements (particularly in mass spectrometry instrumentation as well as quantitation and separation technologies) have allowed impressive progress, which was evident in the First Conference on Proteomics of Protein Degradation and Ubiquitin Pathways in Vancouver (http://ppdup.org/) (Fig. 1).
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PMID:Gold for ubiquitin in Vancouver: First Conference on Proteomics of Protein Degradation and Ubiquitin Pathways held June 6-8, 2010 in Vancouver, University of British Columbia, organized By Lan Huang, Thibault Mayor, and Peipei Ping. 2083 21

Sumoylation, the covalent attachment of SUMO (Small Ubiquitin-Like Modifier) to proteins, differs from other Ubl (Ubiquitin-like) pathways. In sumoylation, E2 ligase Ubc9 can function without E3 enzymes, albeit with lower reaction efficiency. Here, we study the mechanism through which E3 ligase RanBP2 triggers target recognition and catalysis by E2 Ubc9. Two mechanisms were proposed for sumoylation. While in both the first step involves Ubc9 conjugation to SUMO, the subsequent sequence of events differs: in the first E2-SUMO forms a complex with the target and E3, followed by SUMO transfer to the target. In the second, Ubc9-SUMO binds to the target and facilitates SUMO transfer without E3. Using dynamic correlations obtained from explicit solvent molecular dynamic simulations we illustrate the key roles played by allostery in both mechanisms. Pre-existence of conformational states explains the experimental observations that sumoylation can occur without E3, even though at a reduced rate. Furthermore, we propose a mechanism for enhancement of sumoylation by E3. Analysis of the conformational ensembles of the complex of E2 conjugated to SUMO illustrates that the E2 enzyme is already largely pre-organized for target binding and catalysis; E3 binding shifts the equilibrium and enhances these pre-existing populations. We further observe that E3 binding regulates allosterically the key residues in E2, Ubc9 Asp100/Lys101 E2, for the target recognition.
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PMID:A mechanistic view of the role of E3 in sumoylation. 2086 51

Ubiquitin and SUMO are structurally related protein modifiers that are covalently attached to lysine residues of target proteins. While ubiquitin is traditionally known as a signal for proteasomal degradation, its nondegradative actions are equally important in the control of cellular key processes. Similarly, the SUMO system primarily acts in a nondegradative manner. Accumulating evidence indicates that these nonproteolytic functions of ubiquitin and SUMO are particularly important in the control of the DNA damage response network, which coordinates a set of DNA repair pathways and allows cells to cope with different types of genotoxic stress. In this chapter we will illustrate some key functions of ubiquitin and SUMO in the control of selected DNA repair pathways.
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PMID:Regulatory Functions of Ubiquitin and SUMO in DNA Repair Pathways. 2122 83

Recent findings show that chromatin dynamics and nuclear organization are not only important for gene regulation and DNA replication, but also for the maintenance of genome stability. In yeast, nuclear pores play a role in the maintenance of genome stability by means of the evolutionarily conserved family of SUMO-targeted Ubiquitin ligases (STUbLs). The yeast Slx5/Slx8 STUbL associates with a class of DNA breaks that are shifted to nuclear pores. Functionally Slx5/Slx8 are needed for telomere maintenance by an unusual recombination-mediated pathway. The mammalian STUbL RNF4 associates with Promyelocytic leukaemia (PML) nuclear bodies and regulates PML/PML-fusion protein stability in response to arsenic-induced stress. A subclass of PML bodies support telomere maintenance by the ALT pathway in telomerase-deficient tumors. Perturbation of nuclear organization through either loss of pore subunits in yeast, or PML body perturbation in man, can lead to gene amplifications, deletions, translocations or end-to-end telomere fusion events, thus implicating SUMO and STUbLs in the subnuclear organization of select repair events.
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PMID:Nuclear organization in genome stability: SUMO connections. 2132 8

The ternary complex factor (TCF) Elk-1 is a transcription factor that regulates immediate early gene (IEG) expression via the serum response element (SRE) DNA consensus site. Elk-1 is associated with a dimer of serum response factor (SRF) at the SRE site, and its phosphorylation occurs at specific residues in response to mitogen-activated protein kinases (MAPKs), including c-Jun-N terminal kinase (JNK), p38/MAPK, and extracellular-signal regulated kinase (ERK). This phosphorylation event is critical for triggering SRE-dependent transcription. Although MAPKs are fundamental actors for the instatement and maintenance of memory, and much investigation of their downstream signaling partners have been conducted, no data yet clearly implicate Elk-1 in these processes. This is partly due to the complexity of Elk-1 sub-cellular localization, and hence functions, within neurons. Elk-1 is present in its resting state in the cytoplasm, where it colocalizes with mitochondrial proteins or microtubules. In this particular sub-cellular compartment, overexpression of Elk-1 is toxic for neuronal cells. When phosphorylated by the MAPK/ERK, Elk-1 translocates to the nucleus where it is implicated in regulating chromatin remodeling, SRE-dependent transcription, and neuronal differentiation. Another post-translational modification is the conjugation to SUMO (Small Ubiquitin-like MOdifier), which relocalizes Elk-1 in the cytoplasm. Thus, Elk-1 plays a dual role in neuronal functions: pro-apoptotic within the cytoplasm, and pro-differentiation within the nucleus. To address the role of Elk-1 in the brain, one must be aware of its multiple facets, and design molecular tools that will shut down Elk-1 expression, trafficking, or activation, in specific neuronal compartments. We summarize in this review the known molecular functions of Elk-1, its regulation in neuronal cells, and present evidence of its possible implication in model systems of synaptic plasticity, learning, but also in neurodegenerative diseases.
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PMID:Elk-1 a transcription factor with multiple facets in the brain. 2144 90

Homologous recombination plays an important role in the maintenance of genome integrity. Arrested forks and DNA lesions trigger strand annealing events, called template switching, which can provide for accurate damage bypass, but can also lead to chromosome rearrangements. Advances have been made in understanding the underlying mechanisms for these events and in elucidating the factors involved. Ubiquitin- and SUMO-mediated modification pathways have emerged as key players in regulating damage-induced template switching. Here I review the biological significance of template switching at the nexus of DNA replication and recombination, and the role of ubiquitin-like modifications in mediating and controlling this process.
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PMID:Ubiquitin family modifications and template switching. 2153 41

Sentrin specific proteases (SENPs) are responsible for activating and deconjugating SUMO (Small Ubiquitin like MOdifier) from target proteins. It remains difficult to study this posttranslational modification due to the lack of reagents that can be used to block the removal of SUMO from substrates. Here, we describe the identification of small molecule SENP inhibitors and active site probes containing aza-epoxide and acyloxymethyl ketone (AOMK) reactive groups. Both classes of compounds are effective inhibitors of hSENPs 1, 2, 5, and 7 while only the AOMKs efficiently inhibit hSENP6. Unlike previous reported peptide vinyl sulfones, these compounds covalently labeled the active site cysteine of multiple recombinantly expressed SENP proteases and the AOMK probe showed selective labeling of these SENPs when added to complex protein mixtures. The AOMK compound therefore represents promising new reagents to study the process of SUMO deconjugation.
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PMID:Development of small molecule inhibitors and probes of human SUMO deconjugating proteases. 2170 Feb 8


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