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E2 Ubiquitin/Ubl Conjugating Enzymes


Overview of E2 ubiquitin/Ubl conjugating enzymes

Ubiquitin-conjugating enzymes, also known as E2 enzymes and more rarely as ubiquitin-carrier enzymes, perform the second step in the ubiquitination reaction that targets a protein for degradation via the proteasome. E2 enzymes have a variety of individual and redundant roles in cells and play important roles in target degradation (proteasome pathway) and target modification (non-proteasome pathway) for regulatory purposes. Ub/UBL conjugation is initiated by ATP-dependent E1 enzyme and then transferred to cysteine, the active site of E2 enzyme.

Relationship with other enzymes

Ubiquitin-activating enzymes activate ubiquitin by covalently attaching molecules to cysteine residues at their active sites. The activated protein is then transferred to E2 cysteine. Once bound to ubiquitin, E2 molecules bind to one of several ubiquitin ligases or E3 proteins via a structurally conserved binding region. The E3 molecule binds to the target protein substrate and transfers the lysine residues that pervade the protein from E2 cysteine to the target protein.

Specific cells usually contain only a few types of E1 molecules, a greater diversity of E2s, and very large kinds of E3s. Therefore, the E3 molecule responsible for substrate identification and binding is the substrate specificity mechanism of proteasome degradation. Each type of E2 can be associated with many E3.

Isozymes of E2 ubiquitin/Ubl conjugating enzymes

The following human genes encode ubiquitin-conjugating enzymes:

  • UBE2A

Ubiquitin-conjugating enzyme E2A is a protein that in humans is encoded by the UBE2A gene. UBE2A has a predicted molecular weight of 17 kDa. It is highly expressed in the brain and heart. UBE2A is involved in many cellular processes including protein degradation, transcriptional regulation, and the DNA damage response. Mutations in human UBE2A cause UBE2A deficiency syndrome in males, which is characterized by intellectual disability, seizures, absent speech, and urogenital and skin anomalies.

  • UBE2B

Ubiquitin-conjugating enzyme E2B is a protein encoded by UBE2B gene in humans. It has the predicted molecular weight of 17kDa. UBE2B is located in the nucleus and cytoplasm, and is highly expressed in the brain, heart and testis. UBE2B has an E2-catalyzed core domain with cysteine residues at the active sites necessary to form thioester bonds with ubiquitin. UBE2B also functions with the UBR2 E3 to ubiquitinate Histone H2A. UBE2B plays an important role in spermatogenesis and is necessary for male mice to reproduce. Pathologically, UBE2B is overexpressed in mouse and human breast cancer cell lines and tumors, and is reported to be resistant to chemotherapy drugs.

  • UBE2C

Ubiquitin-conjugating enzyme E2 C is a protein that in humans is encoded by the UBE2C gene. UBE2C is an important medium for mitotic disruption and cell cycle progression. It recognizes TEK sequences in target proteins, such as cyclin A and B, mediates ubiquitination of Lys11-junction and promotes target protein degradation with APC/C, a ubiquitin ligase (E3). UBE2C is overexpressed in many human cancers, and alternative splicing allotypes may lead to uncontrolled cell proliferation and tumor progression.

  • UBE2D1

Ubiquitin-conjugating enzyme E2 D1 is a protein that in humans is encoded by the UBE2D1 gene. UBE2D1 has a conserved E2-catalyzed core domain containing cysteine residues at the active site and interacts with a variety of HECT and RING ubiquitin ligases (E3) to mediate ubiquitination of specific target proteins. UBE2D1 interacts with E3 and E6-AP to bind ubiquitin to tumor suppressor p53. Other protein targets of UBE2D1 include c-Fos, RIP1 and HIF-1. UBE2D1 is associated with protein degradation during cancer and immune response.

  • UBE2E1

Ubiquitin-conjugating enzyme E2 E1 is a protein that in humans is encoded by the UBE2E1 gene. UBE2E1 mediates short life and selective degradation of abnormal proteins. After adding the ubiquitin like protein ISG15 to Lys136, the catalytic activity of UBE2E1 was regulated. During HSV-1 infection, UBE2E1 also interacts with virus E3 and ICP0. In addition, UBE2E1 dependent protein ubiquitination is associated with polyglutamine disease, such as ataxia.

  • UBE2G1

Ubiquitin-conjugating enzyme E2 G1 is a protein that in humans is encoded by the UBE2G1 gene. It is reported that UBE2G1 and CRL4 (Cdt2) ubiquitin ligase (E3) together promote the ubiquitination and degradation of Cdt1. The decreased expression of UBE2G1 in medulloblastoma tumors was also reported, suggesting that UBE2G1 could be used as a tumor inhibitor.

  • UBE2H

Ubiquitin-conjugating enzyme E2 H is a protein that in humans is encoded by the UBE2H gene. Human UBE2H is highly expressed in skeleton and myocardium, and has significant expression levels in kidney and placenta, and is expressed at low levels in liver, brain, lung and spleen. In pathology, single nucleotide polymorphisms in UBE2H are associated with autism. In addition, it has been reported that UBE2H is a putative oncogenic gene in liver tumors.

  • UBE2I

Ubiquitin-conjugating Enzyme E2 I is an enzyme that in humans is encoded by the UBE2I gene. The protein encoded by the UBE2I gene constitutes a core machinery in the cell's sumoylation pathway. UBE2I-dependent sumoylation reduces the levels of the stem cell marker, Nanog, implicating it in embryonic stem cell pluripotency maintenance. Sumoylation also regulates the protein levels of tumor suppressors and oncogenes, and UBE2I dysregulation is thought to contribute to the pathogenesis of human cancers. UBE2I has been shown to be targeted by multiple viruses, including HIV and HPV.

References:

  • Nandi D, et al. "The ubiquitin-proteasome system". Journal of biosciences. 2006; 31 (1): 137–55.
  • Townsley FM, et al. "Dominant-negative cyclin-selective ubiquitin carrier protein E2-C/UbcH10 blocks cells in metaphase". Proc Natl Acad Sci U S A. 1997; 94 (6): 2362–7.
  • Nuber U, Scheffner M. "Identification of determinants in E2 ubiquitin-conjugating enzymes required for hect E3 ubiquitin-protein ligase interaction". J. Biol. Chem. March 1999; 274 (11): 7576–82.
  • Machon O, et al. "Yeast two-hybrid system identifies the ubiquitin-conjugating enzyme mUbc9 as a potential partner of mouse Dac". Mech. Dev. 2000; 97 (1–2): 3–12.

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