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  • Review Article
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Ubiquitin-like protein conjugation and the ubiquitin–proteasome system as drug targets

Nature Reviews Drug Discovery volume 10, pages 29–46 (2011)Cite this article

Subjects

Key Points

  • Ubiquitin is a highly conserved 76 amino-acid protein that covalently attaches to protein substrates targeted for degradation by the 26S proteasome. The coordinated effort of a series of enzymes, including an activating enzyme (E1), a conjugating enzyme (E2) and a ligase (E3), uses ATP to ultimately form an isopeptide bond between ubiquitin and a substrate.

  • Another class of enzymes called deubiquitylating enzymes (DUBs) deconstruct these linkages and also have an essential role in ubiquitin function. In addition, ubiquitin-like proteins (UBLs), including NEDD8, SUMO and ISG15, share a characteristic three-dimensional fold with ubiquitin but have their own dedicated enzyme cascades and distinct (although sometimes overlapping) biological functions.

  • The ubiquitin–proteasome system (UPS) and UBL conjugation pathways have important roles in various human diseases, including numerous types of cancer, cardiovascular disease, viral diseases and neurodegenerative disorders. The proteasome inhibitor bortezomib (Velcade; Millennium Pharmaceuticals) is the first clinically validated drug to target the UPS and is approved for the treatment of multiple myeloma. This suggests that other diseases may conceivably be targeted by modulating components of the UPS and UBL conjugation pathways using small-molecule inhibitors.

  • A significant hurdle to identifying drug-like inhibitors of enzyme targets within the UPS and UBL conjugation pathways is the limited understanding of the molecular mechanisms and biological consequences of UBL conjugation.

  • Here, we provide an overview of the enzyme classes in the UPS and UBL pathways that are potential therapeutic targets, and highlight considerations that are important for drug discovery. We also discuss the progress in the development of small-molecule inhibitors, and review developments in understanding of the role of the components of the UPS and the UBL pathways in disease and their potential for therapeutic intervention.

Abstract

The ubiquitin–proteasome system (UPS) and ubiquitin-like protein (UBL) conjugation pathways are integral to cellular protein homeostasis. The growing recognition of the fundamental importance of these pathways to normal cell function and in disease has prompted an in-depth search for small-molecule inhibitors that selectively block the function of these pathways. However, our limited understanding of the molecular mechanisms and biological consequences of UBL conjugation is a significant hurdle to identifying drug-like inhibitors of enzyme targets within these pathways. Here, we highlight recent advances in understanding the role of some of these enzymes and how these new insights may be the key to developing novel therapeutics for diseases including immuno-inflammatory disorders, cancer, infectious diseases, cardiovascular disease and neurodegenerative disorders.

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Figure 1: Overview of the enzymatic cascade involved in ubiquitin-like protein (UBL) conjugation and the ubiqitin–proteasome system (UPS).
Figure 2: Mechanisms of E1 inhibitors identified in studies of different ubiquitin-like protein (UBL) pathways.
Figure 4: Molecular interactions of E2s suggest potential modes of inhibition.
Figure 3: Structural differences among various types of E3 ligases.
Figure 5: Ubiquitin and signalling to nuclear factor-κB (NF-κB).
Figure 6: Protein quality control and neurodegeneration.

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Acknowledgements

The authors thank S. Hill and N. Beavan of FireKite for assistance in the development of this manuscript. L.B., J.L. and R.J.M. thank the Alzheimer's Research Trust and Parkinson's UK for generous support of some of the work reported here.

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Authors and Affiliations

  1. School of Biomedical Sciences, University of Nottingham, NG7 2UH, Nottingham, UK

    Lynn Bedford & R. John Mayer

  2. School of Molecular Medical Sciences, University of Nottingham, NG7 2UH, Nottingham, UK

    James Lowe

  3. Millennium Pharmaceuticals, 40 Landsdowne Street, Cambridge, 02139, Massachusetts, USA

    Lawrence R. Dick & James E. Brownell

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  1. Lynn Bedford
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  3. Lawrence R. Dick
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Correspondence to James E. Brownell.

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Lawrence R. Dick and James E. Brownell are employees of Millennium Pharmaceuticals. Lynn Bedford, James Lowe and R. John Mayer declare no competing financial interests.

Glossary

Ubiquitin

A highly conserved 76 amino-acid protein that can be reversibly attached to other proteins. Key structural features of ubiquitin include its β-grasp fold (a characteristic of all ubiquitin-like proteins), its C-terminal tail and seven lysine residues through which polyubiquitin chains are linked.

Proteasome

The 26S proteasome is a protease complex that degrades polyubiquitylated proteins. It is composed of two subcomplexes: a barrel-shaped 20S core particle containing the protease active sites and two 19S regulatory particles that cap the barrel and control access of substrates to the core.

Nuclear factor-κB

(NF-κB). A transcription factor with a key role in regulating the immune response. NF-κB is involved in cellular responses to stimuli, including stress, cytokines, free radicals, ultraviolet irradiation and bacterial or viral antigens. Misregulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection and improper immune development.

HECT domain

A domain of ∼350 amino acids found at the C terminus of HECT E3s. The HECT domain contains a catalytic cysteine residue that accepts ubiquitin from an E2 to form a thioester intermediate before transferring ubiquitin to a substrate lysine.

U-box

A domain comprising ∼70 amino acids that possesses a tertiary structure resembling the RING finger domain. The major difference is that the Ubox lacks the characteristic zinc-chelating cysteine and histidine residues of the RING finger. Consequently, Ubox E3s use intramolecular interactions other than zinc chelation to maintain the RING finger motif.

RING finger

A domain present in most E3s that is defined by the consensus sequence C-X2-C-X[9-39]-C-X[1-3]-H-X[2-3]-C-X2-C-X[4-48]-C-X2-C (where X means any amino acid). The RING domain coordinates two zinc ions.

Cullin-RING ligases

(CRLs). CRLs are a large family of multi-component E3s consisting of a core cullin protein bound to a RING finger protein (Rbx1/2), and an interchangeable substrate-binding adaptor protein. There are seven cullins and ∼600 adaptors in the human genome. Modification of the cullin subunit by NEDD8 is required for activation of CRL E3 ligase activity.

SCF

SCF complexes are cullin RING ligases (CRLs) that catalyse the ubiquitylation of proteins targeted to the proteasome for degradation. SCF core subunits include the structural protein cullin 1, the RING-finger protein RBX1/2 and the adaptor protein Skp1. This core complex binds to one of the approximately 100 F-box proteins that are responsible for recruiting substrates. F-box proteins are named for the conserved 50 amino acid F-box domain that binds to SKP1. All CRLs, including SCFs, require NEDD8 modification of the cullin subunit for ligase activity.

Rapamycin

Rapamycin (sirolimus) is a macrocyclic antibiotic produced by a bacterium isolated from soil on Easter Island. Rapamycin binds the cytosolic protein FK-binding protein 12 (FKBP12). The rapamcyin–FKBP12 complex inhibits the mTOR (mammalian target of rapamycin) pathway by directly binding mTOR complex1 (mTORC1).

Cysteine proteases

This class of protease uses a cysteine thiol group in its catalytic mechanism. Deprotonation of the cysteine sulphydryl by an adjacent residue (usually histidine) is followed by nucleophilic attack on the peptide carbonyl carbon. A thioester linking the new C terminus to the cysteine thiol is an intermediate of the reaction.

Zinc metalloproteases

A class of protease for which the active sites include two histidine residues that coordinate a zinc ion. During catalysis, the Zn2+ promotes attack of the peptide carbonyl carbon by the oxygen atom of a water molecule at the active site. An active site base facilitates this reaction by extracting a proton from the attacking water molecule.

Autophagy

Literally means 'self-eating'; a highly regulated catabolic process in which cellular proteins and organelles are sequestered in a characteristic double-membrane vesicle called an autophagosome and are then degraded following vesicular fusion with a lysosome.

Endosome–lysosome pathway

Endosomes are membrane- bound vesicles that are involved in protein transport between the plasma membrane, Golgi and lysosomes. In the endocytic pathway, internalized molecules are delivered to early endosomes, where efficient sorting occurs. Some molecules, including recycling receptors, are shunted back to the plasma membrane to be reused. Others, including downregulated receptors, are transported to late endosomes and lysosomes for degradation.

Lewy bodies

Lewy bodies are abnormal protein aggregates that develop inside nerve cells in Parkinson's disease and Alzheimer's disease and some other disorders. They are identified when histology is performed on the brain and appear as spherical masses that displace other cell components.

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Bedford, L., Lowe, J., Dick, L. et al. Ubiquitin-like protein conjugation and the ubiquitin–proteasome system as drug targets. Nat Rev Drug Discov 10, 29–46 (2011). https://doi.org/10.1038/nrd3321

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