E2 ubiquitin conjugating enzyme

Fig. 5.1. The ubiquitin-conjugation pathway. Steps in ubiquitin activation and substrate modification. El, ubiquitin activating enzyme E2, ubiquitin-conjugating enzyme E3, ubiquitin-protein ligase. Atoms involved in the thiol ester and amide bonds are shown.

Okamoto, Y., Ozaki, T., Miyazaki, K., Aoyama, M., Miyazaki, M., and Nakagawara, a. UbcHlO is the cancer-related E2 ubiquitin-conjugating enzyme. Cancer Res. 2003, 63, 4167-73. 

Increasing evidence indicates that accumulation of aberrant or misfolded proteins, protofibril formation, ubiquitin-proteasome system dysfunction, and the direct or indirect consequences of abnormal protein aggregation and accumulation represent deleterious events linked to neurodegeneration (255,256). Ubiquitination is an essential cellular process affected by a multienzyme cascade involving Els (ubiquitin-activating enzymes), E2s (ubiquitin-conjugation enzymes or UBCs), and E3s (ubiquitin-protein Ugases) (12,257) (see Fig. 10.4). 

In the case of E2 ubiquitin conjugating enzymes, the interaction properties of about 200 protein structures were compared [49]. The pairwise similarity matrix was visualized as a dendrogram and a kinemage projection to three-dimensional space (see www.ubiquitin-resource.org). The analysis revealed relations between functional groupings and electrostatic properties at specific parts of the protein structure. 

Tonon, T., Harvey, D., Li, Y., and Graham, I. A. (2003). Isolation of two cDNAs encoding E2 ubiquitin-conjugating enzymes from Pavlova lutheri (Haptophyceae). J. Appl. Phycol. 15, 425-432. 

E1 Ubiquitin-activating enzyme E2 Ubiquitin-conjugating enzyme E3 Ubiquitin ligase (u = Ubiquitin... 

El, ubiquitin-activating enzyme adenylates ubiquitin on its terminal carboxylate with release of PPj. Transfers ubiquitin to a sulfhydryl on the enzyme with release of AMP, forming a thioester bond. E2, ubiquitin-conjugating enzyme receives ubiquitin from El. Ubiquitin is also bound to a sulfhydryl of E2 via a thioester bond. E3, ubiquitin-protein ligase transfers ubiquitin from E2 to the e-amino group of a target protein. 

Ubiquitin tags proteins for protein degradation. The ubiquitination requires three different enzymatic activities, a ubiquitin-activating enzyme (El), a ubiquitin-conjugating enzyme (E2 or Ubc) and a ubiquitin ligase (E3). The action of all three enzymes leads to the establishment of a poly-ubiquitin chain on target proteins which are then recognized and proteolyzed by the 26S proteasome. 

Ubiquitin-conjugating enzyme E2, catalytic domain homologs... 

Loeick, K. L., et al., RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination. Proc Natl Acad Sci USA, 1999, 96(20), 11364-9. 

Ito, K., et al., N-Terminally extended human ubiquitin-conjugating enzymes (E2s) mediate the ubiqui-tination of RING finger proteins, ARA54 and RNE8. Eur J Biochem,... 

Cook, W. J., Jeffrey, L. C., Sullivan, M. L, and Vierstra, R. D. Three-dimensional structure of a ubiquitin-conjugating enzyme (E2)./. Biol. 

D. A., Matunis, M. j., and Lima, C. D. Structural basis for E2-mediated SUMO conjugation revealed by a complex between ubiquitin-conjugating enzyme Ubc9 and RanGAPl. Cell 2002, 108, 345-56. 

Beeleth, E. S. and Pickart, C. M. Mechanism of ubiquitin conjugating enzyme E2—230K catalysis involving a thiol relay Biochemistry 1995, 35, 1664-71. 

Nuber, U., Schwarz, S., Kaiser, P., Schneider, R. and Scheffner, M. Cloning of human ubiquitin-conjugating enzymes UbcH6 and UbcH7 (E2-F1) and characterization of their interaction with E6-AP and RSP5. J Biol Chem 1996, 271, 2795-800. 

Activation of ubiquitin by El requires ATP. El transfers the activated ubiquitin to an E2. Of the three classes of ubiquitin-conjugating enzymes (UBCs), El is the least physiologically regulated. In addition, because El activates ubiquitin, which is attached to all the substrates degraded by the ubiquitin-proteasome pathway, there is no substrate specificity in the action of this enzyme. E2s are more selective and believed to interact with specific E3s. Based on our knowledge of ubiquitination reaction, it can be asserted that E3 are the enzymes that possess substrate specificity. 

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