Ubiquitination, of proteins

Regulating mono-ubiquitination of proteins by DUBs is important in histone modification where ubiquitination is thought to modulate chromatin structure and transcriptional activity. Normally, about 10% of the histone core octomers contain ubiquitinated histones and the ubiquitin is removed at mitosis by DUB activity. UBP8 has been demonstrated to regulate the ubiquitination of histone H2B, which is important in transcriptional activation of many genes [88]. 

Natural products have recently been shown to interfere with specific steps in both the ubiquitination and de-ubiquitination of proteins, effectively preventing their recognition and degradation by the 26S proteasome. Panepophenanthrin (20), isolated from the mushroom Panus radis and himeic acid A (21), isolated from a marine strain of Aspergillus sp., have been shown to interfere with the ubiquitin-activating function of El enzymes. In this ATP-driven process, an adenylated ubiquitin-AMP intermediate is first formed. This ubiquitin intermediate then forms an activated ubiquitin-Cys thioester in the active site of El. Both compounds have been shown to interfere with the formation of the adenylated ubiquitin-AMP intermediate that is required to form the activated ubiquitin thioester. 

Another important finding is that many neurodegenerative diseases are characterized by aberrant protein phosphorylation and ubiquitination (Thomas et al., 2009). Thus, disruption of the phosphorylation of neurotransmitter receptors and hyperphosphorylation of t-protein has been implicated in impaired memory function in AD. Similarly, AD also involves aberrant accumulation of proteins that are normally degraded by the ubiquitin-proteasome system. It is suggested that phosphorylation and ubiquitination of proteins can serve biomarkers for neurodegenerative diseases (Thomas et al., 2009). 

The Nobel Prize in Chemistry 2004 was awarded to A. Ciechanover, A. Hershko, and I. Rose for their work on protein degradation by ubiquitin (ubiquitination of proteins). For additional information, see the review of the first two winners (Hershko and Ciechanover, 1998) and the Nobel Conference on the ubiquitin system (Rose, 2005). Enantiomer (+)-hexylitaconic acid was isolated for the first time in the terrestrial species Aspergillus niger, it is a regulator of plant growth (Isogai et al, 1984). 

Himeic add A is a y-pyrone, produced by the culture of an Aspergillus sp. assodated with Japanese mussels Mytilus edulis, which inhibits one of the three enzymes (El ubiq-uitin-adivating enzyme) involved in the ubiquitination of proteins. Himeic acids B and C, also isolated from the culture medium, are much less active (Tsrikamoto et al., 2005). 

WW domains (named after the one letter abbreviation for the amino acid tryptophan) are small regions of around 30 residues, which, like SH3 domains, bind to polyproline sequences. These sequences often contain the consensus sequence PPXY or PPLP. Examples of proteins that contain WW domains include Nedd4 E3 ubiquitin ligase (Fig. 1) and IQGAP1. 

Multiprotein complex that catalyses ATP-dependent degradation of proteins tagged with ubiquitin. 

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)... 

Small Ubiquitin-like modifier (SUMO) is a conserved protein that is ubiquitously expressed in eukaryotes and is essential for viability. It serves as a reversible posttranslational modifier by forming an isopeptide bond with lysine residues in many target proteins, in a catalytic process termed SUMOylation. SUMOylation of proteins results in altered inter- or intramolecular interactions of the modified target (Fig. 1). 

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. 

Protein modification by the covalent attachment of ubiquitin chains serves as a signal to mark proteins for the degradation by a multicatalytic proteinase complex called the proteasome. Thus the ubiquitin proteasome system (UPS) controls the stability of proteins in a... 

APC is active from mid-M phase (anaphase) to the end of G1 phase and required for disconnecting sister chromatids and exit from M-Phase to Gl. The complex mediates the ubiquitination of Securin and Cyclin B. Degradation of these proteins, which block mitotic progression, promotes anaphase onset and exit from mitosis. 

Marchese A, Benovic JL. Agonist-promoted ubiquitination of the G protein-coupled receptor CXCR4 mediates lysosomal sorting. J Biol Chem 2001 276(49) 4550SM5512. 

Johnsson, N., and Varshavsky, A. (1994). Split ubiquitin as a sensor of protein interactions in vivo. Proc. Natl. Acad. Sci. USA 91, 10340-10344. 

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