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NEDD8
NEDD8 is a protein that in humans is encoded by the ''NEDD8'' gene. (in ''saccharomyces cerevisiae'' this protein is known as Rub1) This ubiquitin-like (UBL) protein becomes covalently conjugated to a limited number of cellular proteins, in a process called NEDDylation similar to ubiquitination. Human NEDD8 shares 60% amino acid sequence identity to ubiquitin. The primary known substrates of NEDD8 modification are the cullin subunits of cullin-based E3 ubiquitin ligases, which are active only when NEDDylated. Their NEDDylation is critical for the recruitment of E2 to the ligase complex, thus facilitating ubiquitin conjugation. NEDD8 modification has therefore been implicated in cell cycle progression and cytoskeletal regulation. Activation and conjugation As with ubiquitin and SUMO, NEDD8 is conjugated to cellular proteins after its C-terminal tail is processed. The NEDD8 activating E1 enzyme is a heterodimer composed of APPBP1 and UBA3 subunits. The APPBP1/UBA3 enzyme has homolog ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
NEDD8 Activating E1 Enzyme
NEDD8 is a protein that in humans is encoded by the ''NEDD8'' gene. (in ''saccharomyces cerevisiae'' this protein is known as Rub1) This ubiquitin-like (UBL) protein becomes covalently conjugated to a limited number of cellular proteins, in a process called NEDDylation similar to ubiquitination. Human NEDD8 shares 60% amino acid sequence identity to ubiquitin. The primary known substrates of NEDD8 modification are the cullin subunits of cullin-based E3 ubiquitin ligases, which are active only when NEDDylated. Their NEDDylation is critical for the recruitment of E2 to the ligase complex, thus facilitating ubiquitin conjugation. NEDD8 modification has therefore been implicated in cell cycle progression and cytoskeletal regulation. Activation and conjugation As with ubiquitin and SUMO, NEDD8 is conjugated to cellular proteins after its C-terminal tail is processed. The NEDD8 activating E1 enzyme is a heterodimer composed of APPBP1 and UBA3 subunits. The APPBP1/UBA3 enzyme has homolog ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
APPBP1
NEDD8-activating enzyme E1 regulatory subunit is a protein that in humans is encoded by the ''NAE1'' gene. Function The protein encoded by this gene binds to the beta-amyloid precursor protein. Beta-amyloid precursor protein is a cell surface protein with signal-transducing properties, and it is thought to play a role in the pathogenesis of Alzheimer's disease. In addition, the encoded protein can form a heterodimer with UBE1C and bind and activate NEDD8, a ubiquitin-like protein. This protein is required for cell cycle progression through the S/M checkpoint. Three transcript variants encoding different isoforms have been found for this gene. APPBP1 (Amyloid Precursor Protein-Binding Protein 1) binds to the Amyloid Precursor Protein (APP) carboxy terminal domain. APPBP1 is a multi-functional protein with activities in neuronal tissues. APPBP1 also bonds with UBA3 (ubiquitin-like protein-activating enzyme 3) to form the NEDD8 activating enzyme (NAE). Activated NEDD8 is an en ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Pevonedistat
Pevonedistat (MLN4924) is a selective NEDD8 inhibitor. It is being investigated as a cancer treatment, e.g. for mantle cell lymphoma (MCL). Target of pevonedistat NEDD8-activating enzyme (NAE) is a heterodimeric molecule consisting of amyloid beta precursor protein-binding protein 1 (APPBP1) and ubiquitin-like modifier activating enzyme 3 ( UBA3). Material was copied from this source, which is available under Creative Commons Attribution 4.0 International (CC BY 4.0)license. As reviewed by Xu et al., in a first step NAE binds ATP and NEDD8 and catalyzes the formation of a NEDD8-AMP intermediate. This intermediate binds the adenylation domain of NAE. NEDD8-AMP reacts with the catalytic cysteine in UBA3 during which NEDD8 is transferred to the catalytic cysteine, resulting in a high energy thioester linkage. NAE then binds ATP and NEDD8 to generate a second NEDD8-AMP, forming a fully loaded NAE carrying two activated NEDD8 molecules (i.e., one as a thioester and the other as ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
NEDDylation
Neddylation (also NEDDylation) is the process by which the ubiquitin-like protein NEDD8 is conjugated to its target proteins. This process is analogous to ubiquitination, although it relies on its own E1 and E2 enzymes. No NEDD8-specific E3 has yet been identified and it is possible that the Neddylation system relies on E3 ligases with dual specificity. NEDD8 NEDD8 (neural-precursor-cell-expressed developmentally down-regulated 8) is a protein involved in the regulation of cell growth, viability and development. Neddylation process NEDD8 links itself to a protein through an isopeptide linkage between its carboxy-terminal glycine and the lysine of the substrate. The neddylation of the substrate causes in a structural change, and there are three main biochemical effects that result. First, neddylation can cause a conformational change in the substrate which may restrict molecular movement and the positioning of different binding partners. Second, it can cause the target protein to ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Neddylation
Neddylation (also NEDDylation) is the process by which the ubiquitin-like protein NEDD8 is conjugated to its target proteins. This process is analogous to ubiquitination, although it relies on its own E1 and E2 enzymes. No NEDD8-specific E3 has yet been identified and it is possible that the Neddylation system relies on E3 ligases with dual specificity. NEDD8 NEDD8 (neural-precursor-cell-expressed developmentally down-regulated 8) is a protein involved in the regulation of cell growth, viability and development. Neddylation process NEDD8 links itself to a protein through an isopeptide linkage between its carboxy-terminal glycine and the lysine of the substrate. The neddylation of the substrate causes in a structural change, and there are three main biochemical effects that result. First, neddylation can cause a conformational change in the substrate which may restrict molecular movement and the positioning of different binding partners. Second, it can cause the target protein to ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Ubiquitin-like Protein
Ubiquitin-like proteins (UBLs) are a family of small proteins involved in post-translational modification of other proteins in a cell, usually with a regulatory function. The UBL protein family derives its name from the first member of the class to be discovered, ubiquitin (Ub), best known for its role in regulating protein degradation through covalent modification of other proteins. Following the discovery of ubiquitin, many additional evolutionarily related members of the group were described, involving parallel regulatory processes and similar chemistry. UBLs are involved in a widely varying array of cellular functions including autophagy, protein trafficking, inflammation and immune responses, transcription, DNA repair, RNA splicing, and cellular differentiation. Discovery Ubiquitin itself was first discovered in the 1970s and originally named "ubiquitous immunopoietic polypeptide". Subsequently, other proteins with sequence similarity to ubiquitin were occasionally reported i ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Ubiquitination
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A. The addition of ubiquitin to a substrate protein is called ubiquitylation (or, alternatively, ubiquitination or ubiquitinylation). Ubiquitylation affects proteins in many ways: it can mark them for degradation via the proteasome, alter their cellular location, affect their activity, and promote or prevent protein interactions. Ubiquitylation involves three main steps: activation, conjugation, and ligation, performed by ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), and ubiquitin ligases (E3s), respectively. The result of this sequential cascade is to bind ubiquitin to lysine residues on the protein substrate via an isopeptide bond, cy ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Cullin
Cullins are a family of hydrophobic scaffold proteins which provide support for ubiquitin ligases (E3). All eukaryotes appear to have cullins. They combine with RING proteins to form ''Cullin-RING ubiquitin ligases'' (CRLs) that are highly diverse and play a role in myriad cellular processes, most notably protein degradation by ubiquitination. The human genome contains eight cullin genes * CUL1, part of SCF complex * CUL2, part of ECS complex (Elongin C - CUL2 - SOCS-box) * CUL3, part of CUL3-BTB complex * CUL4A * CUL4B * CUL5 * CUL7 * CUL9, also known as PARC There is also a more distant member called ANAPC2 (or APC2), part of the Anaphase-promoting complex. CUL1, 2, 3, 4A, 4B, 5 and 7 each form part of a multi-subunit ubiquitin complex. Cullin-RING ubiquitin ligases Cullin-RING ubiquitin ligases (CRLs), such as Cul1 (SCF) play an essential role in targeting proteins for ubiquitin-mediated destruction; as such, they are diverse in terms of composition and function, regu ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, responding to stimuli, providing structure to cells and organisms, and transporting molecules from one location to another. Proteins differ from one another primarily in their sequence of amino acids, which is dictated by the nucleotide sequence of their genes, and which usually results in protein folding into a specific 3D structure that determines its activity. A linear chain of amino acid residues is called a polypeptide. A protein contains at least one long polypeptide. Short polypeptides, containing less than 20–30 residues, are rarely considered to be proteins and are commonly called peptides. The individual amino acid residues are bonded together by peptide bonds and adjacent amino acid residues. The sequence of amino acid residue ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Non-homologous End Joining
Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair(HDR), which requires a homologous sequence to guide repair. NHEJ is active in both non-dividing and proliferating cells, while HDR is not readily accessible in non-dividing cells. The term "non-homologous end joining" was coined in 1996 by Moore and Haber. NHEJ is typically guided by short homologous DNA sequences called microhomologies. These microhomologies are often present in single-stranded overhangs on the ends of double-strand breaks. When the overhangs are perfectly compatible, NHEJ usually repairs the break accurately. Imprecise repair leading to loss of nucleotides can also occur, but is much more common when the overhangs are not compatible. Inappropriate NHEJ can lead to translocations and telomere fusion, hallmarks ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Genome Instability
Genome instability (also genetic instability or genomic instability) refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. Genome instability does occur in bacteria. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy. The sources of genome instability have only recently begun to be elucidated. A high frequency of externally caused DNA damage can be one source of genome instability since DNA damage can cause inaccurate translesion DNA synthesis past the damage or errors in repair, leading to mutation. Another source of genome instability may be epigenetic or mutational reductions in expression of DNA repair genes. Because endogenous (metabolically-caused) DNA damage is very fr ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Cancer Epigenetics
Cancer epigenetics is the study of epigenetics, epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than mutation, genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of gene expression, expression of genes that occurs about 10 times more frequently by transcription silencing (caused by epigenetic promoter hypermethylation of CpG site#Methylation, silencing, cancer, and aging, CpG islands) than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 Genetic hitchhiking, hitchhiker or passenger mutations. However, in ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
