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Review
. 2009 Mar 26;458(7237):422-9.
doi: 10.1038/nature07958.

Origin and function of ubiquitin-like proteins

Mark Hochstrasser  1
Affiliations
Review

Origin and function of ubiquitin-like proteins

Mark Hochstrasser. Nature. .

Abstract

Eukaryotic proteins can be modified through attachment to various small molecules and proteins. One such modification is conjugation to ubiquitin and ubiquitin-like proteins (UBLs), which controls an enormous range of physiological processes. Bound UBLs mainly regulate the interactions of proteins with other macromolecules, for example binding to the proteasome or recruitment to chromatin. The various UBL systems use related enzymes to attach specific UBLs to proteins (or other molecules), and most of these attachments are transient. There is increasing evidence suggesting that such UBL-protein modification evolved from prokaryotic sulphurtransferase systems or related enzymes. Moreover, proteins similar to UBL-conjugating enzymes and UBL-deconjugating enzymes seem to have already been widespread at the time of the last common ancestor of eukaryotes, suggesting that UBL-protein conjugation did not first evolve in eukaryotes.

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Figures

Figure 1
Figure 1
The ubiquitin (U)-protein conjugation cycle. For ubiquitin (and at least some other Ubls), an E3 ligase is usually necessary to stimulate ubiquitin transfer from the E2 to a substrate, generally to a lysine ε-amino group. Additional ubiquitin molecules can be added either to other lysine side chains on the substrate or to ubiquitin itself, the latter leading to polymeric ubiquitin chains. Additional E3s can help assemble ubiquitin chains on substrates; when they act in this way, they are sometimes called “E4s”. Ubiquitin-substrate modifications are transient and can be removed by deubiquitylating enzymes or DUBs (or more generally, Ubl-specific proteases or ULPs). In addition, ubiquitin and most Ubls are synthesized in precursor forms, and the C-terminal extensions are also removed by DUBs or ULPs (not depicted).
Figure 2
Figure 2
Polyubiquitin-tagged proteins are often targeted for proteasome-mediated degradation. The ubiquitin-proteasome pathway is responsible for the degradation of hundreds, and probably thousands, of different proteins. Many of these substrates are regulatory proteins, such as transcription factors or cell cycle regulators, while others are misfolded or otherwise aberrant proteins that must be eliminated to prevent their aggregation or toxicity. A polyubiquitin-modified protein is the form most commonly targeted to the proteasome. Ubiquitin receptors either in the proteasome regulatory particle (RP, blue) of the 26S proteasome or adaptor proteins that associate reversibly with both polyubiquitylated proteins and specific proteasomal subunits (not shown) allow binding of the proteolytic substrate to the proteasome. ATPases within the RP unfold the substrate and translocate it into the 20S proteasome core particle (CP, red), which houses the proteolytic sites in an interior chamber. The substrate is cleaved to small peptides. Ubiquitin itself is normally recycled by DUBs that bind to or are intrinsic to the RP.
Figure 3
Figure 3
Cellular processes that depend on ubiquitin conjugation. Protein attachment to a single ubiquitin allows recognition by a subset of ubiquitin-binding domains (UBDs) in target proteins, and this is important in the indicated general processes. Often a single, specific lysine is modified. Different polyubiquitin chains are thought to have different structures that allow discrimination among other UBDs, although other contextual cues, such as the cellular location where the modification occurs, may also help dictate the physiological consequences of the polyubiquitin attachment. Lys48-linked chains are most commonly associated with proteasomal binding and degradation. Not shown here are ubiquitin chains with mixed linkages or multi-site ubiquitylation of the substrate.
Figure 4
Figure 4
General functions of Ubl tagging. a. Ubl conjugation facilitates protein association by providing an additional binding site. The classic example of this type of regulation is polyubiquitin modification of proteins, which can then bind specific UBD receptors in the proteasome. b. Ubl conjugation causes a conformational change that enhances binding (as shown) or inhibits binding to a target site. For instance, SUMO attachment to thymine-DNA glycosylase (TDG) triggers a conformational change in TDG that lowers its affinity for DNA. c. Modification by one Ubl helps recruit a factor that is different from the protein that would be recruited were the substrate modified by another type of Ubl. These modifications may be mutually exclusive and can potentially involve the same attachment site. The modification of proliferating cell nuclear antigen (PCNA), a DNA replication and recombination protein, by SUMO, ubiquitin, or ubiquitin polymers causes PCNA to bind distinct factors. d. Ubl conjugation directly blocks an interaction between two proteins. A potential example of this is the sumoylation of the vaccinia A40R protein, which prevents association and aggregation between A40R monomers. Other possible variations on these basic mechanisms are not shown.
Figure 5
Figure 5
Uba4 and Urm1, at the crossroads of Ubl-protein modification and sulfur transfer. Two modes of Uba4 activity are depicted: In the cycle on the left, Uba4 functions as a sulfurtransferase, transferring sulfur from a persulfide formed on its rhodanese-homology domain (RHD) to the C-terminus of Urm1, yielding a Urm1 thiocarboxylate (bottom, middle). The sulfur is ultimately transferred to a specific subset of tRNAs. On the right, Uba4 catalyzes transfer of Urm1 to protein substrates (Sub) through a hypothetical Uba4-Urm1 thioester intermediate (middle right). Although it is possible that the Urm1-Uba4 acyl disulfide (bottom left) functions in Urm1-protein modification, it is difficult to explain the requirement for the E1-like domain cysteine residue in such a scheme. Nfs1 is a cysteine desulfurase that mobilizes sulfur from cysteine.
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