E3 protein

Figure 2. Protein interaction domains are used by E3 protein-ubiquitin ligases to recruit substrates for ubiquitination, as well as E2 enzymes. Ubiquitination targets contain specific peptide motifs which bind interaction domains in the E3 protein/complex. These interactions can require phosphorylation on tyrosine (pTyr) or threonine (pThr), or the presence of proline-rich motifs (PPXY). The papilloma vims E6/E6AP complex can recognize substrates that contain PDZ domains, which bind a C-terminal motif in the E6 viral protein. See text for details.

Figure 3. The EBV protein LMP2A binds the SH2 domains of the Lyn and Syk B cell tyrosine kinases, and the WW domains of the AIP4 E3 protein-ubiquitin ligase. The protein-protein interactions elicited by the viral protein lead to the ubiquitination and destabilization of Lyn (and potentially other B cell proteins), which may contribute to the inhibition of BCR signaling in latently infected cells.

Winberg, G., Matskova, L., Chen, F., Plant, P., Rotin, D., Gish, G., Ingham, R., Emberg, I., and Pawson, T. (2000). Latent membrane protein 2A of Epstein-Barr virus binds WW domain E3 protein-ubiquitin ligases that ubiquitinate B-cell tyrosine kinases. Mol Cell Biol 20, 8526-35. 

Although most eukaryotes have only one or a small number of distinct El enzymes, all eukaryotes have many distinct E2 and E3 enzymes. Moreover, there appears to be only a single family of evolutionarily related E2 proteins but many distinct families of E3 proteins. Although the E3 component provides most of the substrate specificity for ubiquitination, the multiple combinations of the E2-E3 complex allow for more finely tuned substrate discrimination. 

Three examples demonstrate the importance of E3 proteins to nor-mal cell tunction. Proteins that are not broken down owing to a de-fective E3 may accumulate to create a disease of protein aggregation such as juvenile and early-onset Parkinson disease. A defect in another member of the E3 family causes Angelman syndrome, a severe neurological disorder diaracterized by mental retardation, absence of speech, uncoordinated movement, and hyperactivity. Conversely, uncontrolled protein turnover can create dangerous pathological conditions. For example, human papilloma virus (HPV) encodes a protein that activates a specific E3 enzyme. The enzyme ubiquitinates the tumor suppressor p53 and other proteins that control DNA repair, which are then destroyed. The activation of this E3 enzvme is observed in more than 90 /u of cervical carcinomas. Thus, the... 

L-protein The fiavin adenine dinucieotide-requiring protein of the giycine cieavage system, which functions to reoxidize dihydroiipoamide after each turnover, in various bacteria it is identicai with the E3 protein. Lipoyltransferase A protein that cataiyzes the transfer of the iipoyi group from iipoyi-AMP - or other activated forms of the moieouie - to LCPs. 

Four adenovirus proteins have been proposed to contribute to protection of infected cells from TNF-mediated cytolysis the E1B/19K protein (reviewed in White 1998) and three E3 proteins, 14.7K, 10.4K, and 14.5K (Wold et al. 1995) found in all human Ad subtypes examined (Fig. 1). The latter two act as a complex. 

TNF-Induced Upregulation of E3 Protein Expression Keeping Up with Host Cytokines... 

Overexpression of FasL, FADD, or FLICE with Ad vectors induces apoptosis that can be inhibited by coexpression of the Ad5 14.7K protein. In this system, the 14.7K protein was shown to bind to FLICE, suggesting that 14.7K might interfere with Fas- and TNF-mediated apoptosis by inhibiting the activation of FLICE (Chen et al. 1998). However, cells infected with a mutant virus lacking all E3 proteins except 14.7K and 12.5K are still sensitive to Fas-mediated cell death. Thus a functional inhibition of FLICE during normal Ad2 infection was not confirmed (Elsing and Burgert 1998 Horwitz 2001). 

Benedict CA, Norris PS, Prigozy TI, Bodmer J-L, Mahr JA, Garnett CT, Martinon F, Tschopp J, Gooding LR, Ware CF (2001) Three adenovirus E3 proteins cooperate to evade apoptosis by TRAIL receptor-1 and 2. J Biol Chem 276 3270-3278... 

Hermiston TW, Hellwig R, Hierholzer JC, Wold WS (1993) Sequence and functional analysis of the human adenovirus type 7 E3-gpl9K protein from 17 clinical isolates. Virology 197 593 600 Hoffman P, Carlin C (1994) Adenovirus E3 protein causes constitutively internalized epidermal growth factor receptors to accumulate in a prelysosomal compartment, resulting in enhanced degradation. Mol Cell Biol 14 3695-3706... 

Wold, W.S. and Gooding, L.R., Adenovirus region E3 proteins that prevent cytolysis by cytotoxic T cells and tumor necrosis factor. Mol Biol. Med., 6,433,1989. 

Vlasak R, Luytjes W, Leider J, Spaan W, Palese P (1988) The E3 protein of bovine coronavirus is a receptor-destroying enzyme with acetylesterase activity. J Virol 62 4686 690... 

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