Ubiquitin-binding domains (UBDs) are

protein domain In molecular biology, a protein domain is a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist o ...

s that recognise and

bind BIND () is a suite of software for interacting with the Domain Name System (DNS). Its most prominent component, named (pronounced ''name-dee'': , short for ''name daemon''), performs both of the main DNS server roles, acting as an authoritative ...

non-

covalent A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atom ...

ly to

ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. F ...

through protein-protein interactions. As of 2019, a total of 29 types of UBDs had been identified in the human

proteome The proteome is the entire set of proteins that is, or can be, expressed by a genome, cell, tissue, or organism at a certain time. It is the set of expressed proteins in a given type of cell or organism, at a given time, under defined conditions. ...

. Most UBDs bind to ubiquitin only weakly, with

binding affinities In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a mole ...

in the low to mid

μM The micrometre ( international spelling as used by the International Bureau of Weights and Measures; SI symbol: μm) or micrometer (American spelling), also commonly known as a micron, is a unit of length in the International System of Uni ...

range. Proteins containing UBDs are known as ubiquitin-binding proteins or sometimes as "ubiquitin receptors".

Structure

Most UBDs are of small size (often less than 50

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

s) and adopt many different

protein fold A protein superfamily is the largest grouping ( clade) of proteins for which common ancestry can be inferred (see homology). Usually this common ancestry is inferred from structural alignment and mechanistic similarity, even if no sequence similar ...

s from multiple fold classes, including all- alpha, all-

beta Beta (, ; uppercase , lowercase , or cursive ; grc, βῆτα, bē̂ta or ell, βήτα, víta) is the second letter of the Greek alphabet. In the system of Greek numerals, it has a value of 2. In Modern Greek, it represents the voiced labi ...

, and alpha/beta folds. Many UBDs can be roughly classified into four broad categories: alpha-helical structures (in some cases as small as a single helix, as in the

ubiquitin-interacting motif In molecular biology, the Ubiquitin-Interacting Motif (UIM), or 'LALAL-motif', is a sequence motif of about 20 amino acid residues, which was first described in the 26S proteasome subunit PSD4/RPN-10 that is known to recognise ubiquitin. In additi ...

);

zinc finger A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) in order to stabilize the fold. It was originally coined to describe the finger-like appearance of a hypothesized struct ...

pleckstrin homology Pleckstrin homology domain (PH domain) or (PHIP) is a protein domain of approximately 120 amino acids that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton. This domain can bind phosph ...

(PH) domains; and domains similar to those in ubiquitin-conjugating (also known as E2)

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

s. Other UBDs not fitting these categories can be

SH3 domain The SRC Homology 3 Domain (or SH3 domain) is a small protein domain of about 60 amino acid residues. Initially, SH3 was described as a conserved sequence in the viral adaptor protein v-Crk. This domain is also present in the molecules of phosp ...

s, PFU domains, and other structures. Small helical structures are the most common, and examples include ubiquitin-associated domains (UBA), CUE domains, the

(UIM), the motif interacting with ubiquitin (MIU), and the VHS protein domain.

Binding mechanism

Many UBDs of the UBA family bind to ubiquitin via a

hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, ...

patch centred on a particular isoleucine residue (the "Ile44 patch"), although binding to other surface patches has been observed, for example the "Ile36 patch".

Zinc finger A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) in order to stabilize the fold. It was originally coined to describe the finger-like appearance of a hypothesized struct ...

UBDs have a broader range of binding modes including interactions with

polar Polar may refer to: Geography Polar may refer to: * Geographical pole, either of two fixed points on the surface of a rotating body or planet, at 90 degrees from the equator, based on the axis around which a body rotates *Polar climate, the cli ...

residues. Because many UBDs have a common or overlapping ubiquitin interaction surface, their interactions are often mutually exclusive; due to

steric clash Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivity of ions ...

es, more than one UBD cannot physically interact with the same Ile44-centered hydrophobic patch on a single ubiquitin molecule. Most UBDs described to date bind to monoubiquitin and thus do not show a linkage-preference for the differently linked ubiquitin chains. There are, however, a handful of known, linkage-specific UBDs, that can specifically differentiate between the eight different ubiquitin linkages. This is important as the different linkage types are thought to signal for different molecular processes and linkage-specific recognition of these chains ensures the appropriate cellular response.

References

{{reflist, 30em Protein domains