Ubiquitin-like proteins

SUMOl (Small Ubiquitin-like modifier 1) Sentrin SMT3C (suppressor of MIF2 mutations 3) GMP1 (GAP-Modifiying Protein 1) Ubll (Ubiquitin-like protein 1) PIC1 (PML interacting protein 1)... 

Hoeller D, Hecker CM, Dikic I (2006) Ubiquitin and ubiquitin-like proteins in cancer pathogenesis. Nat Rev Cancer 6 776-788... 

Ubiquitin-El Ubiquitin-activating enzyme UbL Ubiquitin-like protein... 

M. Cloning of a cDNA which encodes a novel ubiquitin-like protein, Biochem Biophys Res Commun 1993, 195, 393-399. 

Hochsteassee, M. Evolution and function of ubiquitin-like protein-conjugation systems, Nat Cell Biol 2000, 2, E153-157. 

The structure of the APPBP1-UBA3-NEDD8-ATP complex reveals the basis for selective ubiquitin-like protein activation by an El, Mol Cell 2003, 32, 1427-1437. 

Rao-Naik, C., delaCruz, W., Laplaza, J. M., Tan, S., Callis, J., and Fisher, A. J. The rub family of ubiquitin-like proteins. Crystal structure of Arabidopsis rubl and expression of multiple rubs in Arabidopsis, J Biol Chem 1998, 273, 34976-34982. 

E2 Enzymes Dedicated to Ubiquitin-like Proteins (UbLs)... 

Kuez, T. et al. Cytoskeletal regulation by the NeddS ubiquitin-like protein modification pathway. Science 2002, 295, 1294-8,... 

Moeimoto, M., Nishida, T., Honda, R. and Yasuda, H. Modification of cullin-1 by ubiquitin-like protein NeddS enhances the activity of SCE(skp2) toward p27(kipl). Biochem Biophys Res Commun 2000, 270, 1093-6. 

Soon after it was shown that ubiquitin is conjugated to proteins, it was determined that this was a reversible process and deubiquitinating enzymes, or DUBs, could remove ubiquitin from ubiquitinated proteins [18, 19]. As the genes for ubiquitin and ubiquitin-like proteins were identified it became clear that all ubiquitin family members were synthesized as proproteins and processed to reveal the C-terminal glycylglycine of the active proteins [20]. Based on this information, DUBs were defined as proteases that cleave at the C-terminus of ubiquitin or ubiquitin-like proteins to reverse conjugation to target proteins and also process the proproteins. 

The ubiquitin-7ike specific proteases (ULPs) are a third class of DUB first thought to act only on SUMO-related ubiquitin-like proteins. There are two yeast ULPs and seven human ULPs (also called sentrin specific proteases, or SENPs). Further analysis determined that ULPs have little or no activity on ubiquitin substrates, but one (SENPS) acts on NeddS [26, 37, 38]. Despite acting on non-ubiquitin substrates,... 

The central feature that defines all DUBs is that they recognize and act at the C-terminus of the ubiquitin or ubiquitin-like domain. All mature ubiquitin and ubiquitin-like proteins have a C-terminal gly-gly motif and DUB cleavage releases leaving groups attached to the carboxyl group of the C-terminal glycine. With the exception of the JAMM metalloproteases, DUB catalysis starts with the nucleophilic attack of the catalytic cysteine on the carbonyl carbon of the scissile bond to... 

One important function of DUBs is the processing of ubiquitin or ubiquitin-like proteins to their mature forms. Ubiquitin is expressed in cells as either linear poly-ubiquitin or N-terminally fused to certain ribosomal proteins [79, 80]. These gene products are processed by DUBs to separate the ubiquitin into monomers and expose the gly-gly motif at the G-terminus. Many DUBs process linear polyubiquitin or Ub-fusion proteins in vitro, but this processing appears to take place cotransla-tionally in vivo and is extremely rapid. This makes analysis difficult and leaves unanswered the question of which DUBs actually perform this function in vivo. Multiple DUBs may be able to perform this processing at a physiologically relevant level since DUB deletions rarely shows processing defects [81]. 

The most promising tools developed for this sort of analysis are active-site-directed irreversible inhibitors of DUBs. These inhibitors are ubiquitin or ubiquitin-like proteins chemically modified at the C-terminus by an electrophilic moiety such as a Michael acceptor or alkyl halide. The modified ubiquitin can be incubated with a purified DUB or a cell lysate containing DUB activity. Ubiquitin vinyl sul-fone (UbVS) is one such irreversible inhibitor because the vinyl sulfone moiety reacts with the active-site cysteine of the DUB, forming a thioether linkage. The covalent adduct is stable and can be detected in a variety of ways. Labeling of DUBs is specific, as only a DUB active-site cysteine will efficiently react with the vinyl sulfone moiety. 

H. P., and Yeh, E. T. Characterization of NEDD8, a developmentally down-regulated ubiquitin-like protein, J Biol Chem, 1997, 272, 28557-62. 

Johnson, E. S., Sghwienhorst, I., Dohmen, R. j., and Blobel, G. The ubiquitin-like protein Smt3p is activated for conjugation to other proteins by an Aoslp/Uba2p heterodimer, Embo J, 1997, 36, 5509-19. 

C. D., Ploegh, H. L., and Ovaa, H. Specific and covalent targeting of conjugating and deconjugating enzymes of ubiquitin-like proteins. 

Flsasser, S. et al. Proteasome subunit Rpnl binds ubiquitin-like protein domains. Nat Cell Biol 2002, 4, 725-30. 

Saeki, Y., Sone, T., Toh-e, A., and Yokosawa, FI. Identification of ubiquitin-like protein-binding subunits of the 26S proteasome. Biochem Biophys Res Commun 2002, 296, 813-9. 

Elsasser, S., Gali, R. R., Schwickaet, M., Iaesen, C. N., Leggett, D. S., Muller, B., Feng, M. T., Tubing, F., Dittmar, G. a., and Finley, D. Proteasome subunit Rpnl binds ubiquitin-like protein domains. Nat. Cell Biol. 2002, 4, 725-730. 

Kim, K. I. and Zhang, D. E., 1SG15, not just another ubiquitin-like protein, Biochem. Biophys. Res. Commun., 2003, 307, 431. 

---