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Ubiquitin-binding domains

Key Points

  • Nine ubiquitin-binding domains (UBDs) have been identified and characterized so far by various approaches. There are probably more UBDs yet to be discovered.

  • Interactions between UBDs and ubiquitin are typically weak (Kd = 2–500 μM), and are likely to be dynamic and tightly regulated in cells.

  • Although all UBDs bind to a similar surface of ubiquitin — a hydrophobic patch that includes Ile44 of ubiquitin — the structures of different UBDs are surprisingly diverse.

  • Many UBDs are required for the ubiquitylation of the protein within which they are carried. The mechanism and functions of UBD-dependent ubiquitylation have not yet been defined.

  • There are only a few defined functions for UBDs in cellular proteins, which include a role in polyubiquitin chain formation, roles as receptors for polyubiquitin chains that target proteins to the proteasome for degradation, and proposed roles as receptors for ubiquitin sorting signals in the late endosomal pathway.

Abstract

Ubiquitin-binding domains (UBDs) are a collection of modular protein domains that non-covalently bind to ubiquitin. These recently discovered motifs interpret and transmit information conferred by protein ubiquitylation to control various cellular events. Detailed molecular structures are known for a number of UBDs, but to understand their mechanism of action, we also need to know how binding specificity is determined, how ubiquitin binding is regulated, and the function of UBDs in the context of full-length proteins. Such knowledge will be key to our understanding of how ubiquitin regulates cellular proteins and processes.

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Figure 1: Ubiquitin modifications.
Figure 2: Ubiquitin–ubiquitin-binding-domain complex structures.
Figure 3: Models for the function of coupled ubiquitin binding and ubiquitylation.
Figure 4: The proposed role of ubiquitin receptors in the late endosomal pathway.

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Acknowledgements

We thank M. French, W. Lin, I. Radhakrishnan and W. Sundquist for their constructive comments on this manuscript. Work in our laboratories is supported by grants from the National Institutes of Health.

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Correspondence to Linda Hicke.

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DATABASES

Swiss-Prot

NEDD8

SUMO

ubiquitin

FURTHER INFORMATION

Christopher Hill's laboratory

Linda Hicke's laboratory

Pfam (Protein families database of alignments and HMMs)

SMART (Simple Modular Architecture Research Tool)

Glossary

PROTEASOME

A large 2.5-MDa multisubunit protein complex that binds to and subsequently degrades polyubiquitylated proteins.

POLYUBIQUITIN CHAIN

A string of ubiquitin molecules that are attached to each other by covalent bonds between the C terminus of one ubiquitin and any one of seven lysine residues of the adjacent ubiquitin (Lys48 and Lys63 are two of the key sites for polyubiquitin conjugation).

UBIQUITIN RECEPTOR

A ubiquitin-binding-domain-containing protein that is known to bind directly to ubiquitin and probably binds to ubiquitin signals in partner protein(s) rather than participating in ubiquitylation reactions.

S5A/RPN10

(subunit 5a (mammals)/regulatory particle non-ATPase-10 (yeast)). A ubiquitin-interacting-motif-containing protein that is a stable subunit of the proteasome. It functions as one of the receptors for polyubiquitylated proteins that are destined for degradation.

HIDDEN MARKOV MODEL

A probability-based model that is used to make predictions about a set of uncharacterized sequences. The predictions are made on the basis of the conservation information that has been derived from a set of interrelated sequences.

YEAST TWO-HYBRID SCREEN

A method that is used to identify protein–protein interactions. It exploits the ability of two interacting proteins to bring the DNA-binding and DNA-activation fragments of a transcription factor together to trigger the expression of a reporter gene.

TOM1

(target of v-myb-1). A mammalian protein that contains both VHS (Vps27, HRS, STAM) and GAT (Gga and Tom1) domains and that probably functions in transport through the endosomal pathway.

ZINC FINGER

A protein domain in which the tertiary structure of the polypeptide chain is determined by coordination around a zinc ion.

NEDD8

(neuronal-precursor-cell-expressed developmentally downregulated protein-8). A protein with sequence (57% identity) and structural similarity to ubiquitin that modifies subunits of specific E3 ubiquitin-ligase complexes to increase their ubiquitylation activity.

UBIQUITIN-LIKE PROTEINS (Ubls).

Motifs of 45–80 amino acids that have significant sequence and structural similarity to ubiquitin. Examples include discrete proteins and domains that are located within larger proteins.

ENDOCYTIC PATHWAY

The pathway that is followed by proteins that are internalized from the cell surface. Cargo proteins are either recycled back to the plasma membrane or move through early and late endosomal compartments to the lysosome.

EPS15

(epidermal growth factor receptor substrate-15). An important component of the endocytic machinery that functions in cargo sorting and vesicle formation at the plasma membrane.

EPS15-HOMOLOGY DOMAINS (EH domains).

Domains of 95 amino acids that mediate protein–protein interactions and are found predominantly, but not exclusively, in proteins that are involved in endocytosis. Many EH domains bind to motifs that contain an Asn-Pro-Phe (NPF) sequence.

SH3 DOMAINS

(Src-homology-3 domains). Protein domains of 50 amino acids that bind primarily to short Pro-rich (PXXP) target sequences.

SH2 DOMAIN

(Src-homology-2 domain). Domains of 100 amino acids that are found in diverse proteins. They can bind to a phosphorylated tyrosine residue of a partner protein.

ENVELOPED VIRUSES

Viruses that bud from infected cells and are surrounded by a lipid bilayer that is derived from the plasma membrane of the host cell.

TSG101

(tumour susceptibility gene-101). A UEV (ubiquitin-conjugating enzyme variant)-domain-containing protein that is required for the sorting of ubiquitylated cargo in the endocytic pathway.

GAG

A viral protein that carries a so-called 'late' domain that is required for the efficient budding of a virus from an infected cell. Low levels of ubiquitylated Gag have been detected in virus particles.

P47

A protein that binds to Cdc48 (also known as p97/VCP) to promote membrane fusion during the reassembly of the nuclear envelope, endoplasmic reticulum and Golgi complex after mitosis. The ubiquitin-associated (UBA) domain of p47 is required for p47–Cdc48 fusion activity.

RAD23

A protein that has ubiquitin-like and ubiquitin-associated domains and that functions as a receptor to shuttle ubiquitylated proteins to the proteasome.

MMS2

A UEV (ubiquitin-conjugating enzyme variant)-containing protein that binds to Ubc13 (ubiquitin-conjugating enzyme-13) to form an E2 complex that functions specifically in the formation of Lys63-linked polyubiquitin chains.

HECT DOMAIN E3S

(homology to E6-AP C-terminus domain E3s). These enzymes receive activated ubiquitin from an E2 and transfer it directly to a substrate protein. Unlike other E3s, these proteins have an active-site Cys residue that forms a thiolester linkage to ubiquitin during ubiquitin transfer from an E2 to a substrate.

EPSIN

(Eps15-interacting protein). An essential component of the endocytic machinery that functions in cargo sorting and vesicle formation at the plasma membrane.

UBL-UBA PROTEINS

A family of proteins that carry an N-terminal ubiquitin-like (Ubl) domain and one or two ubiquitin-associated (UBA) domains. Some members are involved in the proteasome-mediated degradation of ubiquitylated proteins.

SORTING SIGNAL

This is usually a linear amino acid sequence or a post-translational modification that specifies the cellular location or destination of an integral membrane protein.

SECRETORY PATHWAY

The path (which is typically the endoplasmic reticulum (ER) to the Golgi to the lysosome or plasma membrane) that is followed by proteins that enter the ER during translation. This pathway transports proteins to their ultimate cellular or extracellular locations.

LYSOSOME

An acidic organelle that contains digestive enzymes. In this organelle, proteins and other cellular molecules are degraded into their building-block subunits (for example, proteins into amino acids).

MULTIVESICULAR ENDOSOME/BODY

An organelle in the late endocytic pathway that is filled with vesicles that have budded from the limiting membrane into the lumen. Fusion of a multivesicular endosome with a lysosome delivers the vesicles into the lysosome lumen, where they are degraded.

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Hicke, L., Schubert, H. & Hill, C. Ubiquitin-binding domains. Nat Rev Mol Cell Biol 6, 610–621 (2005). https://doi.org/10.1038/nrm1701

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