Polyubiquitination

Ubiquitin/Proteasome. Figure 2 Functional consequences of ubiquitin linkage. Substrates (blue bars) are linked via lysine residues (K) to ubiquitin or ubiquitin chains, (a) Attachment of chains connected via Lysines in position 48 of ubiquitin (K48) targets substrates for proteasomal degradation. In contrast modification of one (b) or multiple (c) lysines by a single ubiquitin molecule mediates novel protein interactions or initiates endocytosis. Conjugation of K63-linked polyubiquitin (d) alters protein function and can also serve as a signal for endocytosis. 

Proteasomal degradation also plays an essential role in the activation of cellular signaling pathways. A prototype for this is the control of NF-kB signaling, which has a pivotal role in inflammatory responses. Upon stimulation the inhibitory IicBa protein is phos-phorylated and thereby becomes a target substrate for K48-polyubiquitination. Proteasomal degradation of IkBu releases the transcription factor NF-kB, which subsequently translocates to the nucleus and activates specific target genes. 

Mayor, T., Lipford, J.R., Graumann, J., Smith, G.T., Deshaies, R.J. (2005). Analysis of polyubiquitin conjugates reveals that the rpnlO substrate receptor contributes to the turnover of multiple proteasome targets. Mol. Cell. Proteomics 4, 741-751. 

Two distinct structural elements play a role in the ubiquitination of a target protein (i) the E3 recognition site and (ii) the anchoring residue of the polyubiquitin chain. In most cases, it is believed, though it has been shown for only a few proteins, that the first ubiquitin moiety is transferred to an -NH2 group of an internal lysine residue in the substrate. The N-terminal domain of the target protein has attracted attention both as an E3 recognition domain and, recently, as a ubiquitination site. 

Hershko, a. and Heller, H. Occurrence of a polyubiquitin structure in ubiquitin-protein conjugates. 

Deng, L, Wang, C., Spencer, E., Yang, L, Braun, A., You, f., Slaughter, C., Pickart, C., and Chen, Z. J. Activation of the IkappaB kinase complex by TRAE6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain, Cdl 2000, 103, 351—361. 

Nishikawa, H., et al., Mass spectro-metric and mutational analyses reveal Lys-6-linked polyubiquitin chains catalyzed by BRCAl-BARDl ubiquitin ligase. / Biol Chem, 2004, 279(6), 3916-24. 

Hofmann, R. M. and C. M. Pickart, Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair. Cell, 1999, 96(5), 645-53. 

The U-box family of E3s bind E2s through the small U-box domain [119]. Some U-box E3s do not seem to have their own cognate substrates, but instead promote polyubiquitination of the substrates of other E3s [120]. Other U-box E3s have defined cognate substrates and behave in a canonical marmer [121, 122]. 

Z. -Q. The NeddS-conjugated ROCl-CULl core ubiquitin ligase utilizes NeddS charged surface residues for efficient polyubiquitin chain assembly catalyzed by Cdc34. J. Biol. Chem. 

VanDemaek, a. P., Hofmann, R. M., Tsui, C., Pickaet, C. M., and WoLBEEGEE, C. Molecular insights into polyubiquitin chain assembly crystal structure of the Mms2/Ubcl3 heterodimer. Cell 2001, 105, 711-20. 

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