C O N T E N T S
Ubiquitin is a small regulatory protein that is ubiquitous in eukaryotes. Ubiquitination (or Ubiquitylation) refers to the Post-translational modification of a protein by the covalent attachment (via an isopeptide bond) of one or more ubiquitin monomers. Ubiquitin (originally, Ubiquitous Immunopoeitic Polypeptide) was first identified in 1975 as an 8.5 kDa protein of unknown function expressed universally in living cells. The basic functions of ubiquitin and the components of the ubiquitination pathway were elucidated in the early 1980s in groundbreaking work performed by Aaron Ciechanover, Avram Hershko and Irwin Rose for which the Nobel Prize in Chemistry was awarded in 2004.
Poly-ubiquitination, the process in which a chain of at least four ubiquitin peptides are attached to a lysine on a substrate protein, most commonly results in the degradation of the substrate protein via the proteasome. Apparently, at least four ubiquitins are required on a substrate protein in order for the proteasome to bind and therefore degrade the substrate (though there are examples of non-ubiquitinated proteins being targeted to the proteasome).
Mono-ubiquitination, the process in which a single ubiquitin peptide is bound to a substrate, initiates cell signaling by allowing other proteins that contain ubiquitin binding domains to interact with the mono-ubiquitinated substrate. Mono-ubiquitination has been associated with targeting of proteins to the endoplasmic reticulum, for example.
The ubiquitylation system was initially characterised as an ATP-dependent proteolytic system present in cellular extracts. 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. 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. Soon after APF-1-protein conjugation was characterised, APF-1 was identified as ubiquitin. The carboxyl group of the C-terminal glycine residue of ubiquitin (Gly76) was identified as the moiety conjugated to substrate lysine residues.
Ubiquitin is a small protein that occurs in all eukaryotic cells. Its main function is to mark other proteins for destruction, known as proteolysis. Several ubiquitin molecules attach to the condemned protein (polyubiquitination), and it then moves to a proteasome?, a barrel-shaped structure where the proteolysis occurs. Ubiquitin can also mark transmembrane proteins (for example, receptors) for removal from membranes and fulfill several signalling roles within the cell.
Ubiquitin consists of 76 amino acids and has a molecular mass of about 8500 Da. It is highly conserved among eukaryotic species: Human and yeast ubiquitin share 96% sequence identity. The human ubiquitin sequence is:
The process of marking a protein with ubiquitin (ubiquitylation or ubiquitination) consists of a series of steps:
Transfer can occur in two ways:
In many cases, ubiquitin molecules are further added on to previously-conjugated ubiquitin molecules to form a polyubiquitin chain. If the chain is longer than 3 ubiquitin molecules, the tagged protein is rapidly degraded by the 26S-proteasome into small peptides (usually 3-24 amino acid residues in length). Ubiquitin moieties are cleaved off the protein by deubiquitinating enzymes and are recycled for further use.
Cell-surface transmembrane molecules that are tagged with ubiquitin are often mono-ubiquitinated, and this modification alters the subcellular localization of the protein, often targeting the protein for destruction in lysosomes.
The ubiquitin pathway is thought to be the method of cellular egress for a number of retroviruses, including HIV and Ebola, but the exact mechanism by which this occurs has yet to be deduced.
The Anaphase-promoting complex (APC) and the SCF complex (for Skp1-Cullin-F-box protein complex) are two examples of multi-subunit E3s involved in recognition and ubiquitination of specific target proteins for degradation by the proteasome.
Antibodies to ubiquitin are used in histology to identify abnormal accumulations of protein inside cells that are markers of disease. These accumulations are called inclusion bodies. Examples of such abnormal inclusions in cells are
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