Ubiquitin system

Hershko A, Ciechanover A The ubiquitin system. Annu Rev Biochem 1998 67 425. 

Brief History of Protein Degradation and the Ubiquitin System... 

T., Hellman, U., Schwaetz, A. L., and Ciechanovee, A. The Tumor Suppressor Protein pl6 and the Human Papillomavirus oncoprotein E7-58 are Naturally Occurring Lysine-Less Proteins that are Degraded by the Ubiquitin System Direct Evidence for Ubiquitination at the N-Terminal Residue. J. Biol. Chem., 2004, 279, 41414-41421. 

Liakopoulos, D., Doenges, G., Matuschewski, K., and Jentsch, S. A novel protein modification pathway related to the ubiquitin system, Embo J199S, 17, 2208-2214. 

Fig. 4.1. Fundamentals of the ubiquitin system. Adapted from Ref [5]. Figure 4.1 shows the fundamentals of the ubiquitin system. (1) Ubiquitin is synthesized in linear chains or as the N-terminal fusion with small ribosomal subunits that are cleaved by de-ubiquitylating enzymes to form the active protein. Ubiquitin is then activated in an ATP-dependent manner by El where a thiolester linkage is formed. It is then transthiolated to the active-site cysteine of an E2. E2s interact with E3s and with substrates and mediate either the indirect (in the case of HECT E3s) or direct transfer of ubiquitin to substrate. A number of factors can affect this process. We know that interactions with Hsp70 can facilitate ubiquitylation in specific instances and competition for lysines on substrates with the processes of acetylation and sumoylation may be inhibitory in certain instances. (2) For efficient proteasomal targeting to occur chains of ubiquitin linked internally through K48 must be formed. This appears to involve multiple...

Ulrich, H. D. Degradation or maintenance actions of the ubiquitin system on eukaryotic chromatin. Eukaryotic Cell 2002, 1, 1—10. 

Ubiquitin system JAMMing in the name of the lid, Curr Biol, 2002, 12, R815-7. 

Hershko, A., Cieghanover, A., and Varshavsky, A. Basic Medical Research Award. The ubiquitin system. Nat Med 2000, 6, 1073-81. 

When a novel homology domain has been discovered, it is possible to store the corresponding domain descriptor (profile or HMM) in a number of dedicated domain databases, which can be used to analyze newly identified sequences for their domain content [9, 10]. Several competing domain- and motif-databases exist, including PROSITE, PFAM, SMART, and Superfam, which contain descriptors for most, if not all, of the known domains involved in the ubiquitin system [11-14]. Recently, a new meta-database named INTERPRO has been established, which tries to combine the descriptors of several domain databases under a single user interface [15]. Pointers to the very useful search engines of the domain databases are provided in Table 12.1. 

When looking at the examples shown in Figure 12.1, or at the large set of proteins not shown here, two general trends are obvious (i) the ubiquitin domain tends to be localized at the extreme N-terminus, and (ii) the host protein is typically involved in the ubiquitin system. The first observation has been interpreted as an evolutionary remnant of earlier ubiquitin-fusion proteins [40]. As mentioned above, ubiquitin is typically expressed as a precursor protein, wherein the ubiquitin moiety is localized at the N -terminus and has to be liberated by dedicated ubiquitin hydrolases. It is certainly possible that many extant proteins with ubiquitin-like domains used to be alternative ubiquitin precursors but have lost their cleavability. The second observation will be discussed in more detail in Sections 12.5.1 and 12.5.2. 

The UBA domain was initially identified as a short homology region of about 40 residues, which is found in a multitude of proteins involved in the ubiquitin system [46]. An alignment of some representative UBA domains is shown in Figure 12.2. For a more comprehensive overview, there are a number of excellent reviews... 

EFTsNT A UBA-like domain with a clear role outside of ubiquitin binding is found at the N-terminus of EF-Ts proteins. The relationship of this region to genuine UBA domains is well established as there is a structure of full-length EF-Ts available [67]. Nevertheless, this domain is widespread in bacteria and archaea, which obviously lack a proper ubiquitin system. The physiological role of the EFTsNT domain is rather in the binding to the elongation factor EF-Tu, which has no resemblance to ubiquitin. 

---