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Ubiquitin is a small (8.5 kDa) regulatory protein that has been found in almost all tissues (ubiquitously) of eukaryotic organisms. The addition of ubiquitin to a substrate protein is called ubiquitination or ubiquitylation. The protein modifications can be either a single ubiquitin protein (monoubiquitination) or a chain of ubiquitin (polyubiquitination). Ubiquitin (originally, ubiquitous immunopoietic polypeptide) was first identified in 1975[1] as an 8.5 kDa protein of unknown function expressed in all eukaryotic cells. The ubiquitination system was initially characterised as an ATP-dependent proteolytic system present in cellular extracts.
Ubiquitination (or ubiquitylation) is an enzymatic post-translational modification in which a ubiquitin protein is attached to a substrate protein. Ubiquitination requires three types of enzyme: ubiquitin-activating enzymes, ubiquitin-conjugating enzymes, and ubiquitin ligases, known as E1s, E2s, and E3s, respectively. Activation: Ubiquitin is activated in a two-step reaction by an E1 ubiquitin-activating enzyme, which is dependent on ATP.
Conjugation: E2 ubiquitin-conjugating enzymes catalyse the transfer of ubiquitin from E1 to the active site cysteine of the E2 via a trans(thio)esterification reaction. In the ubiquitination cascade, E1 can bind with many E2s, which can bind with hundreds of E3s in a hierarchical way. Monoubiquitination is the addition of one ubiquitin molecule to one substrate protein residue. Polyubiquitination is the formation of a ubiquitin chain on a single lysine residue on the substrate protein. Lysine 48-linked polyubiquitin chains target proteins for destruction, by a process known as proteolysis.
Lysine 63-linked chains are not associated with proteasomal degradation of the substrate protein. Differently linked chains have specific effects on the protein to which they are attached, caused by differences in the conformations of the protein chains. Multi-monoubiquitination can mark transmembrane proteins (for example, receptors) for removal from membranes (internalisation) and fulfil several signalling roles within the cell. Ubiquitination of histone H2AX is involved in DNA damage recognition of DNA double-strand breaks. Histones can be ubiquitinated and this is usually in the form of monoubiquitination (although polyubiquitinated forms do occur). Deubiquitinating enzymes (DUBs) oppose the role of ubiquination by removing ubiquitin from substrate proteins. Ubiquitin-binding domains (UBDs) are modular protein domains that non-covalently bind to ubiquitin, these motifs control various cellular events. Angelman syndrome is caused by a disruption of UBE3A, which encodes a ubiquitin ligase (E3) enzyme termed E6-AP.
Von Hippel-Lindau syndrome involves disruption of a ubiquitin E3 ligase termed the VHL tumor suppressor, or VHL gene. Fanconi anemia: Eight of the thirteen identified genes whose disruption can cause this disease encode proteins that form a large ubiquitin ligase (E3) complex.
Immunohistochemistry using antibodies to ubiquitin can identify abnormal accumulations of this protein inside cells, indicating a disease process. Although ubiquitin is the most-understood post-translation modifier, there is a growing family of ubiquitin-like proteins (UBLs) that modify cellular targets in a pathway that is parallel to, but distinct from, that of ubiquitin. UBLs are structurally similar to ubiquitin and are processed, activated, conjugated, and released from conjugates by enzymatic steps that are similar to the corresponding mechanisms for ubiquitin. CKSAAP_UbSite is SVM-based prediction that employs the composition of k-spaced amino acid pairs surrounding a query site (i.e. The Shipping Weight includes the product, protective packaging material and the actual shipping box. Chicken liver flavor, starch, L-lysine, water, soy lecithin, canola oil, brewer's yeast, glycerin, oat flour, barley flour, rye flour, oat meal, calcium sulfate, maltodextrin, sodium alginate, sorbic acid, propionic acid (a preservative), mixed tocopherol blend (a preservative).


My young Persian is not sneezing anymore, nor does she has a runny nose or a troublesome ear! The ubiquitination bonds are always formed with one of the seven lysine residues as well as the very N-terminal methionine from the ubiquitin molecule. A heat-stable polypeptide present in these extracts, ATP-dependent proteolysis factor 1 (APF-1), was found to become covalently attached to the model protein substrate lysozyme in an ATP- and Mg2+-dependent process.[13] Multiple APF-1 molecules were linked to a single substrate molecule by an isopeptide linkage, and conjugates were found to be rapidly degraded with the release of free APF-1.
UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. This process most commonly binds the last amino acid of ubiquitin (glycine 76) to a lysine residue on the substrate.
In order to perform this reaction, the E2 binds to both activated ubiquitin and the E1 enzyme.
Most commonly, they create an isopeptide bond between a lysine of the target protein and the C-terminal glycine of ubiquitin. Multi-monoubiquitination is the addition of one ubiquitin molecule to multiple substrate residues. Following addition of a single ubiquitin moiety to a protein substrate, further ubiquitin molecules can be added to the first, yielding a polyubiquitin chain.[65] These chains are made by linking the glycine residue of a ubiquitin molecule to a lysine of ubiquitin bound to a substrate. At least four ubiquitin molecules must be attached to a lysine residue on the condemned protein in order for it to be recognised by the 26S proteasome.[68] This is a barrel-shape structure comprising a central proteolytic core made of four ring structures, flanked by two cylinders that selectively allow entry of ubiquitinated proteins. Instead, they allow the coordination of other processes such as endocytic trafficking, inflammation, translation, and DNA repair.[10] In cells, lysine 63-linked chains are bound by the ESCRT-0 complex, which prevents their binding to the proteasome.
K29-, K33-,[75] K63- and M1-linked chains have a fairly linear conformation; they are known as open-conformation chains.
When cell-surface transmembrane molecules are tagged with ubiquitin, the subcellular localization of the protein is altered, often targeting the protein for destruction in lysosomes.
Under normal physiological conditions PCNA is sumoylated (a similar post-translational modification to ubiquitination). Histone ubiquitination alters chromatin structure and allows the access of enzymes involved in transcription. This abnormal peptide, known as UBB+1, has been shown to accumulate selectively in Alzheimer's disease and other tauopathies. These protein accumulations are referred to as inclusion bodies (which is a general term for any microscopically visible collection of abnormal material in a cell). Known UBLs include: small ubiquitin-like modifier (SUMO), ubiquitin cross-reactive protein (UCRP, also known as interferon-stimulated gene-15 ISG15), ubiquitin-related modifier-1 (URM1), neuronal-precursor-cell-expressed developmentally downregulated protein-8 (NEDD8, also called Rub1 in S.
There is also cross-regulation between the various conjugation pathways, since some proteins can become modified by more than one UBL, and sometimes even at the same lysine residue. UBLs are also translated with C-terminal extensions that are processed to expose the invariant C-terminal LRGG.
Prokaryotic ubiquitin-like protein (Pup) serves the same function (targeting proteins for degradations), although the enzymology of ubiquitination and pupylation is different. These 'linking' residues are represented by a "K" or "M" (which is the one-letter amino acid notation of lysine and methionine, respectively) and a number, referring to its position in the ubiquitin molecule.
The E1 binds both ATP and ubiquitin and catalyses the acyl-adenylation of the C-terminus of the ubiquitin molecule. Humans possess 35 different E2 enzymes, whereas other eukaryotic organisms have between 16 and 35. The monoubiquitination of a protein can have different effects to the polyubiquitination of the same protein. Once inside, the proteins are rapidly degraded into small peptides (usually 3–25 amino acid residues in length). This serves as a negative feedback mechanism because often the stimulation of receptors by ligands increases their rate of ubiquitination and internalisation. When DNA is damaged by ultra-violet radiation or chemicals, the SUMO molecule that is attached to a lysine residue is replaced by ubiquitin. Ubiquitin on histones also acts as a binding site for proteins that either activate or inhibit transcription and also can induce further post-translational modifications of the protein.


They are highly specific, as are the E3 ligases that attach the ubiquitin, with only a few substrates per enzyme. For instance, SUMO modification often acts antagonistically to that of ubiquitination and serves to stabilize protein substrates. These modifiers have their own specific E1 (activating), E2 (conjugating) and E3 (ligating) enzymes that conjugate the UBLs to intracellular targets. In contrast to the three-step reaction of ubiquitination, pupylation requires two steps, therefore only two enzymes are involved in pupylation. First, a ubiquitin molecule is bonded by its C-terminus to a specific lysine residue on the target protein.
The carboxyl group of the C-terminal glycine residue of ubiquitin (Gly76) was identified as the moiety conjugated to substrate lysine residues. The ubiquitin protein itself consists of 76 amino acids and has a molecular mass of about 8.5 kDa.
The second step transfers ubiquitin to an active site cysteine residue, with release of AMP. E3 enzymes function as the substrate recognition modules of the system and are capable of interaction with both E2 and substrate. The ubiquitin molecules in open-conformation chains do not interact with each other, except for the covalent isopeptide bonds linking them together. Monoubiquitinated PCNA recruits polymerases that can carry out DNA synthesis with damaged DNA; but this is very error-prone, possibly resulting in the synthesis of mutated DNA. They can cleave both isopeptide (between ubiquitin and lysine) and peptide bonds (between ubiquitin and the N-terminus).
Proteins conjugated to UBLs are typically not targeted for degradation by the proteasome but rather function in diverse regulatory activities. Poly-ubiquitination occurs when the C-terminus of another ubiquitin, will be linked to one of the seven lysine residues or the first methionine on the previously added ubiquitin molecule itself (for example on K48, K29 or M1), forming a chain. In addition to removing ubiquitin from substrate proteins, DUBs have many other roles within the cell.
For example, SUMO shares only 18% sequence identity, but they contain the same structural fold.
Attachment of UBLs might, alter substrate conformation, affect the affinity for ligands or other interacting molecules, alter substrate localization, and influence protein stability. It is highly conserved among eukaryotic species: Human and yeast ubiquitin share 96% sequence identity. E3 enzymes possess one of two domains: the homologous to the E6-AP carboxyl terminus (HECT) domain and the really interesting new gene (RING) domain (or the closely related U-box domain). Altering the chain conformations exposes and conceals different parts of the ubiquitin protein, and the different linkages are recognized by proteins that are specific for the unique topologies that are intrinsic to the linkage.
Ubiquitin is either expressed as multiple copies joined in a chain (polyubiquitin) or attached to ribosomal subunits. As such, these products will reflect a higher Shipping Weight compared to the unprotected product. Only poly-ubiquitination on defined lysines, mostly on K48 and K29, is related to degradation by the proteasome (referred to as the "molecular kiss of death"), while other polyubiquitinations (e.g.
The distances between individual ubiquitin units in chains differ between lysine 63- and 48-linked chains. They also recycle ubiquitin that has been bound to small nucleophilic molecules during the ubiquitination process.
This compact globular beta-grasp fold is found in ubiquitin, UBLs, and proteins that comprise a ubiquitin-like domain, e.g. The UBDs exploit this by having small spacers between ubiquitin-interacting motifs that bind lysine 48-linked chains (compact ubiquitin chains) and larger spacers for lysine 63-linked chains.



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