Ubiquitin

Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e. it occurs ubiquitously. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the 1970s and 1980s. Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A.QQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGGin Proteome (amino acids)AffinityH. sapiens: 21H. sapiens: 14H. sapiens: ?H. sapiens: 25H. sapiens: 16H. sapiens: 98H. sapiens: ?H. sapiens: 71H. sapiens: 28 Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e. it occurs ubiquitously. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the 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 ubiquitination (or, less frequently, ubiquitylation or ubiquitinylation). Ubiquitination 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. Ubiquitination 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, cysteine residues through a thioester bond, serine and threonine residues through an ester bond, or the amino group of the protein's N-terminus via a peptide bond. The protein modifications can be either a single ubiquitin protein (monoubiquitination) or a chain of ubiquitin (polyubiquitination). Secondary ubiquitin molecules are always linked to one of the seven lysine residues or the N-terminal methionine of the previous ubiquitin molecule. These 'linking' residues are represented by a 'K' or 'M' (the one-letter amino acid notation of lysine and methionine, respectively) and a number, referring to its position in the ubiquitin molecule as in K48, K29 or M1. The first ubiquitin molecule is covalently bound through its C-terminal carboxylate group to a particular lysine, cysteine, serine, threonine or N-terminus of the target protein. Poly-ubiquitination occurs when the C-terminus of another ubiquitin, is then linked to one of the seven lysine residues or the first methionine on the previously added ubiquitin molecule, creating a chain. This process repeats several times, leading to the addition of several ubiquitins. 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. on K63, K11, K6 and M1) and monoubiquitinations may regulate processes such as endocytic trafficking, inflammation, translation and DNA repair. The discovery that ubiquitin chains target proteins to the proteasome, which degrades and recycles proteins, was honored with the Nobel Prize in chemistry in 2004. Ubiquitin (originally, ubiquitous immunopoietic polypeptide) was first identified in 1975 as an 8.6 kDa protein of unknown function expressed in all eukaryotic cells. The basic functions of ubiquitin and the components of the ubiquitination pathway were elucidated in the early 1980s at the Technion by Aaron Ciechanover, Avram Hershko, and Irwin Rose for which the Nobel Prize in Chemistry was awarded in 2004. The ubiquitination 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 exists in all eukaryotic cells. It performs its myriad functions through conjugation to a large range of target proteins. A variety of different modifications can occur. The ubiquitin protein itself consists of 76 amino acids and has a molecular mass of about 8.6 kDa. Key features include its C-terminal tail and the 7 lysine residues. It is highly conserved throughout eukaryote evolution; human and yeast ubiquitin share 96% sequence identity. Ubiquitin is encoded in mammals by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. The UBB and UBC genes code for polyubiquitin precursor proteins. Ubiquitin is believed to have descended from prokaryotic proteins similar to ThiS or MoaD. These prokaryotic proteins, despite having little sequence identity (ThiS has 14% identity to ubiquitin), share the same protein fold. These proteins also share sulfur chemistry with ubiquitin. MoaD, which is involved in molybdenum cofactor biosynthesis, interacts with MoeB, which acts like an E1 ubiquitin-activating enzyme for MoaD, strengthening the link between these prokaryotic proteins and the ubiquitin system. A similar system exists for ThiS, with its E1-like enzyme ThiF. It is also believed that the Saccharomyces cerevisiae protein Urm-1, a ubiquitin-related modifier, is a 'molecular fossil' that connects the evolutionary relation with the prokaryotic ubiquitin-like molecules and ubiquitin.