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Ubiquitin-binding domains — from structures to functions

Nature Reviews Molecular Cell Biology volume 10, pages 659–671 (2009)Cite this article

Key Points

  • Ubiquitin is an intracellular signalling molecule that is conjugated to various proteins. Ubiquitin conjugation to itself yields Lys- or Met-conjugated chains, thus expanding its repertoire of signalling networks.

  • Ubiquitin-binding domains (UBDs) are modular elements that bind non-covalently to the protein modifier ubiquitin.

  • Specific ubiquitin–UBD interactions are crucial for the regulation of multiple cellular functions, including protein stability, receptor trafficking, DNA damage responses and inflammatory pathways.

  • UBD preferences for distinct ubiquitin chains of specific length and linkage are mediated through multimeric interactions, sequence context of the UBD and conformational changes following binding.

  • Structures of ubiquitin–UBD complexes have revealed mechanisms of selectivity and specificity in their functional interactions in vivo.

  • Defects in ubiquitin–UBD interactions are relevant for development of disease, such as inflammation and cancer. The new structure-based insights provide strategies for the design of new approaches that can therapeutically target ubiquitin–UBD interaction surfaces.

Abstract

Ubiquitin-binding domains (UBDs) are modular elements that bind non-covalently to the protein modifier ubiquitin. Recent atomic-level resolution structures of ubiquitin–UBD complexes have revealed some of the mechanisms that underlie the versatile functions of ubiquitin in vivo. The preferences of UBDs for ubiquitin chains of specific length and linkage are central to these functions. These preferences originate from multimeric interactions, whereby UBDs synergistically bind multiple ubiquitin molecules, and from contacts with regions that link ubiquitin molecules into a polymer. The sequence context of UBDs and the conformational changes that follow their binding to ubiquitin also contribute to ubiquitin signalling. These new structure-based insights provide strategies for controlling cellular processes by targeting ubiquitin–UBD interfaces.

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Figure 1: Enzymatic cascade that leads to substrate ubiquitylation.
Figure 2: The ubiquitin–UBD network.
Figure 3: Structural diversity contributes to the multiplicity of ubiquitin signalling.
Figure 4: Ubiquitin is recognized by structurally diverse domains.
Figure 5: Multivalent interactions between ubiquitin and UBDs define chain specificity and increase affinity.

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Acknowledgements

We thank M. Bienko, N. Crosetto, D. Hoeller and D. McEwan for constructive comments and critical reading of the manuscript and the members of our laboratories for discussions. We thank X. Chen, N. Crosetto, M. Kawasaki, T. Kensche, S. Rahighi, P. Zhou and S. Skånland for help in making the figures. Research in the I.D. laboratory is supported by the Deutsche Forschungsgemeinschaft and the Cluster of Excellence “Macromolecular Complexes” of the Goethe University Frankfurt (EXC115), in the S.W. laboratory by the Target Protein Research Project of the MEXT, Japan, and in the K.J.W. laboratory by the US National Institutes of Health (CA097004 and CA117888) and the American Cancer Society (RSG-07-186-01-GMC).

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  1. Institute of Biochemistry II and Cluster of Excellence “Macromolecular Complexes”, Goethe University Frankfurt, Theodour-Stern-Kai 7, Frankfurt, D-60590, Germany

    Ivan Dikic

  2. Tumour Biology Program, Mediterranean Institute for Life Sciences, Split, 21000, Croatia

    Ivan Dikic

  3. Department of Immunology, School of Medicine, University of Split, Soltanska 2, Split, 21000, Croatia

    Ivan Dikic

  4. Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, 305-0801, Ibaraki, Japan

    Soichi Wakatsuki

  5. Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, 55455, Minnesota, USA

    Kylie J. Walters

Authors
  1. Ivan Dikic
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  2. Soichi Wakatsuki
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  3. Kylie J. Walters
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Corresponding author

Correspondence to Ivan Dikic.

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DATABASES

Protein Databank

 1AAR

1D3Z

1Q5W

1ZO6

2D3G

2DX5

2FIF

2FUH

2G45

2JF5

2JY6

2W9N

2Z59

FURTHER INFORMATION

Ivan Dikic's homepage

Kylie J. Walter's homepage

Soichi Wakatsuki's homepage

Glossary

26S proteasome

A large protein complex that carries out regulated degradation to control protein lifespan. Proteasome activity is essential for a large range of cellular events, including cell cycle progression, DNA repair, apoptosis and the removal of misfolded proteins.

Endosome

A small vesicle that is formed by endocytosis (invagination) of the plasma membrane, along with surface receptors, and is responsible for sorting internalized proteins and other biomolecules. Depending on the cargoes, endosomes are transported back to the cell surface for recycling, transported to the Golgi apparatus or matured into lysosomes.

β-Sheet

A secondary structural element of proteins, in which the peptide backbone is almost fully extended.

310 Helix

A secondary structural element of proteins, in which a coiled conformation enables the formation of hydrogen bonds between backbone carbonyl and amide groups of amino acids that are three residues apart.

α-Helix

A secondary structural element of proteins, in which a coiled conformation enables the formation of hydrogen bonds between backbone carbonyl and amide groups of amino acids that are four residues apart.

Residual dipolar coupling

(RDC). Dipole–dipole coupling between spin 1/2 nuclei in samples that are partially aligned with an external magnetic field. RDC provides the orientation of bonds between neighbouring atoms relative to the rest of the molecule and can therefore be used in structure determination by NMR spectroscopy.

Zinc finger

A small structural motif in proteins that is stabilized by interactions between amino acid side-chain atoms and a coordinated zinc atom.

Ubiquitin conjugating (UBC) domain

The α/β structural fold of E2 conjugating enzymes that is characterized by a conserved active-site Cys residue, which forms a thiolester bond with ubiquitin.

Plekstrin homology (PH) fold

A structural fold in proteins that is characterized by a distinct pattern of β-strands and an α-helix. This protein family tends to have a core of bulky hydrophobic amino acids.

Ubiquitin-binding zinc finger

(UBZ). A subclass of ubiquitin-binding zinc finger domain that can bind to ubiquitin and control DNA damage responses.

Ubiquitin-associated (UBA) domain

A small structural domain in proteins that is characterized by a three-helix bundle and is typically associated with the ubiquitin pathway.

CUE domain

(Coupling of ubiquitin conjugation to endoplasmic reticulum degradation domain). A protein structural domain that is similar to the UBA domain. CUE domains form a three-helix bundle.

ERAD

(Endoplasmic reticulum-associated degradation). A pathway by which misfolded proteins are transported from the endoplasmic reticulum to the 26S proteasome in the cytosol.

Translesion synthesis polymerase

A member of a group of DNA polymerases that carry out translesion synthesis past DNA lesions. These polymerases, mostly belonging to the Y-family, have an open configuration and can accommodate different damaged bases in their active sites.

UBAN domain

(Ubiquitin binding in ABIN and NEMO domain). An α-helical domain that is present in NEMO, ABINs and optineurin. It binds specifically to linear ubiquitin chains.

Coiled coil

A structural motif in which α-helices coil around each other to enable favourable interactions between amino acid side-chain atoms.

Multivesicular body

(MVB). A specialized endosome that is formed from early and sorting endosomes through invagination of the membrane enriched with surface receptors, resulting in many internalized vesicles. MVBs mature into late endosomes and lysosomes for degradation of internalized surface receptors.

Ubiquitin-binding motif

(UBM). A structural ubiquitin-binding motif that is present in translesion DNA polymerases and is required for proper localization of these enzymes in nuclear replication foci.

Peptidomimetic inhibitor

A chemical or natural compound that mimics a peptide–peptide interaction through a non-peptide bond or structure.

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Dikic, I., Wakatsuki, S. & Walters, K. Ubiquitin-binding domains — from structures to functions. Nat Rev Mol Cell Biol 10, 659–671 (2009). https://doi.org/10.1038/nrm2767

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  • DOI: https://doi.org/10.1038/nrm2767

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