Ubiquitin is a small 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.
A ubiquitin ligase is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate. In simple and more general terms, the ligase enables movement of ubiquitin from a ubiquitin carrier to another thing by some mechanism. The ubiquitin, once it reaches its destination, ends up being attached by an isopeptide bond to a lysine residue, which is part of the target protein. E3 ligases interact with both the target protein and the E2 enzyme, and so impart substrate specificity to the E2. Commonly, E3s polyubiquitinate their substrate with Lys48-linked chains of ubiquitin, targeting the substrate for destruction by the proteasome. However, many other types of linkages are possible and alter a protein's activity, interactions, or localization. Ubiquitination by E3 ligases regulates diverse areas such as cell trafficking, DNA repair, and signaling and is of profound importance in cell biology. E3 ligases are also key players in cell cycle control, mediating the degradation of cyclins, as well as cyclin dependent kinase inhibitor proteins. The human genome encodes over 600 putative E3 ligases, allowing for tremendous diversity in substrates.
ITCH is a HECT domain E3 ubiquitin ligase that is ablated in non-agouti-lethal 18H mice. Itchy mice develop a severe immunological phenotype after birth that includes hyperplasia of lymphoid and hematopoietic cells, and stomach and lung inflammation. In humans ITCH deficiency causes altered physical growth, craniofacial morphology defects, defective muscle development, and aberrant immune system function. ITCH contains a C2 domain, proline-rich region, WW domains, HECT domain, and multiple amino acids that are phosphorylated and ubiquitinated.
E3 ubiquitin-protein ligase NEDD4, also known as neural precursor cell expressed developmentally down-regulated protein 4 is an enzyme that is, in humans, encoded by the NEDD4 gene.
F-box/WD repeat-containing protein 7 is a protein that in humans is encoded by the FBXW7 gene.
Ubiquitin D is a protein that in humans is encoded by the UBD gene, also known as FAT10. UBD acts like ubiquitin, by covalently modifying proteins and tagging them for destruction in the proteasome.
Ubiquitin-conjugating enzyme E2 D2 is a protein that in humans is encoded by the UBE2D2 gene.
NEDD4-like E3 ubiquitin-protein ligase WWP1 is an enzyme that in humans is encoded by the WWP1 gene.
E3 ubiquitin-protein ligase UBR5 is an enzyme that in humans is encoded by the UBR5 gene.
Ubiquitin/ISG15-conjugating enzyme E2 L6 is a protein that in humans is encoded by the UBE2L6 gene.
Tripartite motif-containing protein 25 is a protein that in humans is encoded by the TRIM25 gene.
Activating transcription factor 5, also known as ATF5, is a protein that, in humans, is encoded by the ATF5 gene.
Tripartite motif-containing protein 32 is a protein that in humans is encoded by the TRIM32 gene. Since its discovery in 1995, TRIM32 has been shown to be implicated in a number of diverse biological pathways.
Tripartite motif-containing 22, also known as TRIM22, is a protein which in humans is encoded by the TRIM22 gene.
Ubiquitin-conjugating enzyme E2 E2 is a protein that in humans is encoded by the UBE2E2 gene.
HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2 is a protein that in humans is encoded by the HECW2 gene.
Mitochondrial E3 ubiquitin protein ligase 1 (MUL1) is an enzyme that in humans is encoded by the MUL1 gene on chromosome 1. This enzyme localizes to the outer mitochondrial membrane, where it regulates mitochondrial morphology and apoptosis through multiple pathways, including the Akt, JNK, and NF-κB. Its proapoptotic function thus implicates it in cancer and Parkinson’s disease.
HECT domain E3 ubiquitin protein ligase 4 is a protein that in humans is encoded by the HECTD4 gene.
Probable E3 ubiquitin-protein ligase HERC3 is an enzyme that in humans is encoded by the HERC3 gene. The gene is a member of the HERC family of ubiquitin ligases and encodes a protein with a HECT domain and an RCC1-like domain (RLD). It binds ubiquitin and hPLIC-1/2 via its HECT domain. Alternatively spiced transcript variants encoding multiple isoforms have been observed, and mutations in this gene have been linked to colorectal and gastric carcinomas. The protein is localized in the cytosol and vesicular-like structures containing β-COP, ARF, and Rab5. Since HERC3 can itself be ubiquitinated and degraded by the proteasome, it likely has roles in both vesicular traffic and ubiquitin-dependent processes.
HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 is a protein that in humans is encoded by the HACE1 gene.
