Ubiquitin-protein ligase

Huibregtse, J. M., et al., A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase. Proc Natl Acad Sci USA, 1995, 92(7), 2563-7. 

Zheng, N., et al.. Structure of a c-Cbl-UbcH7 complex RING domain function in ubiquitin-protein ligases. Cell, 2000, 102(4), 533-9. 

Yang, Y., et al., Ubiquitin protein ligase activity of lAPs and their degradation in proteasomes in response to apoptotic stimuli. Science, 2000, 288(5467), 874-7. 

JoAZEiRO, C. A., et al.. The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. Science, 1999,... 

Fang, S., et al., Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. / Biol Chem, 2000, 275(12), 8945-51. 

Fang, S., et al., RING finger ubiquitin protein ligases implications for tumorigenesis, metastasis and for molecular targets in cancer. Semin Cancer Biol, 2003, 13(1), 5-14. 

Fang, S., et al.. The tumor autocrine motility factor receptor, gp78, is a ubiquitin protein ligase implicated in degradation from the endoplasmic reticulum. Proc Natl Acad Sci USA,... 

Suzuki, Y., Y. Nakabayashi, and R. Takahashi, Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes protea-... 

Yamanaka, K., et al., Identification of the ubiquitin-protein ligase that recognizes oxidized IRP2. Nat Cdl Biol, 2003, 5(4), 336-40. 

Imai, Y., M. Soda, and R. Takahashi, Parkin Suppresses Unfolded Protein Stress-induced Cell Death through Its E3 Ubiquitin-protein Ligase Activity. J Biol Chem, 2000, 275(46), 35661-35664. 

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.

From a chemical point of view, the El/ubiquitin thiol ester should be competent to donate ubiquitin to a substrate amino group. In fact, aminoacyl-errzyme thiol esters are used in exactly this way in non-ribosomal polypeptide synthesis, a process that was discovered around the same time as ubiquitin-protein conjugation [5]. In spite of the attractive simplicity of this model, however, biochemical reconstitution studies showed that besides El two additional fractions were required to conjugate ubiquitin to a model substrate. They were called ubiquitin carrier protein (E2) and ubiquitin-protein ligase (E3), respectively, since the respective factors seemed to act sequentially [6]. Interestingly, the E2 factor apparently formed a thiol ester with ubiquitin. Based on these results, Hershko and co-workers proposed the ubiquitin conjugation cascade (Figure 5.1). 

Heeshko, A., Heller, H., Elias, S., and Ciechanovee, A. Components of ubiquitin-protein ligase system. J. Biol. Chem. 1983, 258, 8206-14. 

Dunn, R. and Hicke, L. Domains of the Rsp5 ubiquitin-protein ligase required for receptor-mediated and... 

Zhou, P. and P. M. Howley, Ubiquitination and degradation of the substrate recognition subunits of SCF ubiquitin-protein ligases. Mol Cell, 1998, 2(5), 571-80. 

The E3 ubiquitin-protein ligases represent a large and diverse family of proteins and protein complexes [3]. The human genome alone is estimated to code for hun-... 

ISSj 7 The Structural Biologf of Ubiquitin-Protein Ligases... 

Ubiquitin-protein ligases promote not only the attachment of ubiquitin to the protein substrates but also the extension of the ubiquitin chain. What determines the choice between mono- vs. polyubiquitination is not well understood. It is possible that certain E3s catalyze only mono-ubiquitination. Alternatively, factors other than E3s might be responsible for the attachment of a single ubiquitin. Eor example, ubiquitin-binding accessory proteins have been suggested to block extension of the ubiquitin chain [25], whereas E3-associated ubiquitin hydrolase could trim down the polyubiquitin chain. The identification and characterization of ubiquitin E2 variant proteins (UEVs) have provided an explanation for the assembly of K63-linked polyubiquitin chains [26, 27]. As discussed later, UEVs can be considered as special E3s, with the ubiquitin chain as their substrates. 

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