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Ubiquitination, a proteasomal degradation process, is based on covalent attachment of ubiquitin to a substrate lysine on a target protein, marking the protein for its degradation. This process renews intracellular proteins balancing the rate of degradation with the rate of protein synthesis, resulting in homeostasis. Homeostasis is achieved by eliminating damaged proteins which typically result in disease as they compete with functional proteins for binding sites/partners.
In addition to homeostasis, the process also regulates cell cycle progression, gene transcription, DNA repair, apoptosis and receptor endocytosis, some of which require lysosomal degradation. However, the UPS (ubiquitin proteasome system) differs from the UBL (ubiquitin like system) and from the lysosomal pathway (requiring autophagy for degradation). The 76AA ubiquitin molecule contains 7 lysine residues allowing the formation of isopeptide linked chains or Met1 chains (ubiquitin linked ubiquitin). The predominant linkage being Lys 48 due to its degradation role usually allows polyubiquitination to occur, with the Lys 63 linkage known for its non-degradation role and subsequent activation of pathways such as PKB/AKT. Following the covalent addition of the ubiquitin chain, the regulatory mechanism involves three enzymes in a cascade of activation, conjugation and ligation resulting in the degradation of the target protein by the 26s proteasome.
Initiation of the mechanism occurs through activation of ubiquitin in an ATP dependent manner by E1. A thioester bond results upon activation between the ubiquitin C terminus and an active cysteine on E1. E2, the ubiquitin-conjugating enzyme, then binds with E1, transferring the ubiquitin to E2 at a catalytic cysteine residue. The final enzyme involved in the process, E3, ubiquitin ligase, forms a complex with E2 through an isopeptide bond, facilitating the transfer of ubiquitin to the substrate protein. Formation of this isopeptide bond occurs at the amino group of lysine in the substrate and the C terminal glycine residue of the ubiquitin molecule (Fig.1). Considering E3 is the final enzyme involved in the cascade, it determines specificity of the substrate. With a large number of substrates available, a large ligase family must also exist (>700 members). The E1 family, which typically lack specificity for E2 or E3 only contain 2 members in humans, however the E2 family comprises of 40 members as its main role determines which polyubiquitin chains are catalysed by E3.
Classification of the E3 ligase family is crucial, impacting the mechanism in which conjugation to the substrate occurs. Classification varies but was observed by Francesca Morreale, University of Dundee, Scotland as a 3 member family including: RING (Really Interesting New Gene) and U-box (UFD2 homology), RBR (Ring in-Between Ring) and HECT (homologous to E6-associated protein C-terminus), each with a varying mechanism of action. The most prevalent being, RING, which act as mediators, directly transferring ubiquitin from E2 to the substrate, never binding with ubiquitin itself but acting as a scaffold ensuring a flexible E2 orientation for the substrate. These ligases are comprised of a zinc binding domain and possess the ability to act as monomers, homodimers or heterodimers. Homodimer RING ligases allow the binding of an E2 per monomer, resulting in two E2’s bound. Similarly, U-box ligases contain a RING structure however lacking the zinc domain and potentially act as monomers and homodimers however, their main role involves completing polyubiquitin elongation, previously begun by another ligase. RING ligases are often classified based on their multiple subunit composition such as cullin ring ligases (CRL) comprised of a cullin scaffold or anaphase-promoting complex/cyclosome (APC/C) composed of 19 subunits, including a ring subunit (Apc11) and a cullin-like subunit (Apc2).
HECT ligases function by a varying mechanism comprised of two steps. Ubiquitin forms an intermediate bond with the catalytic cysteine on E3 prior to its transfer to the target protein. This domain, positioned at the C terminus of proteins contains an N-terminal lobe and C-terminal lobe structure, allowing specificity of the substrate and catalysis respectively. Subfamilies such as Nedd4 and HERC exist here due to varying N termini. The final group of ligases, RBR posses the same mechanism of action as the HECT ligase family however, differ in structure. RBR ligases are comprised of two RING structures, one which recruits the E2 molecule (ubiquitin charged) and the second containing the catalytic cysteine. Proteasomal degradation is an irreversible process once the target protein reaches the proteasome. It is comprised of at least one 20s regulatory particle (RP), for substrate recognition and a 19S hollow core particle (CP) typically comprised of alpha and beta subunits, completing the degradation of the unfolded protein. However, prior to this step, ubiquitination is potentially reversible.
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