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  • Review Article
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Ubiquitin and ubiquitin-like proteins as multifunctional signals

Key Points

  • Protein ubiquitylation is a recognized signal for protein degradation. The covalent linkage of a K48-linked polyubiquitin chain to a target protein signals its degradation by the 26S proteasome.

  • It is increasingly realized that ubiquitin conjugation to proteins can be used for many other non-degradative purposes. For example, monoubiquitylation can induce receptor-mediated endocytosis and receptor sorting into multivesicular bodies, and K63-linked polyubiquitin chains can function in signal-transduction cascades.

  • Furthermore, there are many ubiquitin-like proteins that can be conjugated to various proteins to control their activities. All of these ubiqutin-like proteins are characterized by the ubiquitin superfold, despite the fact that some of them have little or no sequence homology to ubiquitin.

  • The ubiquitin superfold can also be genetically built into larger proteins, where it can function to regulate various downstream processes.

  • We currently know about only a small number of the proteins that are modified by ubiquitin and ubiquitin-like proteins (ubiquitons). With modern proteomics, we expect to find that many regulatory proteins are conjugated to ubiquitons to enhance the specificity of protein interactions.

Abstract

Protein ubiquitylation is a recognized signal for protein degradation. However, it is increasingly realized that ubiquitin conjugation to proteins can be used for many other purposes. Furthermore, there are many ubiquitin-like proteins that control the activities of proteins. The central structural element of these post-translational modifications is the ubiquitin superfold. A common ancestor based on this superfold has evolved to give various proteins that are involved in diverse activities in the cell.

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Figure 1: Ubiquitin conjugation and the ubiquitin–proteasome system.
Figure 2: Proposed roles for ubiquitin and SUMO in DNA repair.

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Acknowledgements

We are grateful for the support of the Alzheimer's Research Trust, the Parkinson's Disease Society, and the Biotechnology and Biological Sciences Research Council. We also thank S. Urbé (University of Liverpool, UK) for help with the discussions on ubiquitin and endocytosis.

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Correspondence to R. John Mayer.

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DATABASES

Swiss-Prot

http://us.expasy.org/sprot/

Atg8

Atg12

FAT10

NEDD8

NF-κB

Rad6

Rad18

SUMO

ubiquitin

UBL5

UCRP

POSTER

Ubiquitin and ubiquitin-like proteins

Glossary

MOLYBDOPTERIN

A molecule that coordinates the metal atom molybdenum through its dithiolene group for use in several reactions in the cell.

THIAMINE

A coenzyme for chemical rearrangements that involve the transfer of aldehyde groups between carbon atoms.

ISOPEPTIDE BOND

A peptide bond that links the carboxyl group of the C-terminal glycine of a covalent modifier, for example, ubiquitin, to the ε-amino group of a lysyl residue in a target protein or second ubiquitin molecule.

UBIQUITON

A covalently attachable or genetically built-in ubiquitin superfold.

TRANSLESION SYNTHESIS

DNA synthesis by the DNA polymerases ζ and η over a gap in DNA.

OSTEOCLASTOGENESIS

The generation of osteoclasts, which resorb bone.

PAGET'S DISEASE

A bone-loss condition that is associated with ageing.

MULTIVESICULAR BODIES

Late endosomal organelles that are formed by the invagination of the endosomal membrane to form intralumenal vesicles.

AAA PROTEINS

(ATPases associated with various cellular activities). A superfamily of structurally related proteins (usually hexameric) that control diverse and unrelated functions in the cell.

LYMPHOKINE

A secretory molecule that regulates cells in the immune and inflammatory systems.

SPLICEOSOME

A large dynamic nuclear complex that mediates the excision of pre-mRNA introns and the ligation of exons, thereby generating mature mRNA.

PEROXIREDOXIN

An enzyme that promotes the elimination of peroxides from cells.

PSEUDOHYPHAL GROWTH

A form of growth in yeast that is used for nutrient sensing. It is characterized by the elongation of the cells and their adhesion to each other to form filaments.

RHO GTPASES

A subfamily of small (21 kDa) GTP-binding proteins that are related to Ras and that function as molecular switches to control signal-transduction pathways, for example, in the regulation of endocytic traffic and cytoskeleton function.

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Welchman, R., Gordon, C. & Mayer, R. Ubiquitin and ubiquitin-like proteins as multifunctional signals. Nat Rev Mol Cell Biol 6, 599–609 (2005). https://doi.org/10.1038/nrm1700

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