Ubiquitin-binding domains (UBDs) are protein domains that recognise and bind non- covalently to ubiquitin through protein-protein interactions. As of 2019, a total of 29 types of UBDs had been identified in the human proteome. 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 m ...

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 Unit ...

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 acids) and adopt many different protein folds from multiple fold classes, including all-

alpha Alpha (uppercase , lowercase ; grc, ἄλφα, ''álpha'', or ell, άλφα, álfa) is the first letter of the Greek alphabet. In the system of Greek numerals, it has a value of one. Alpha is derived from the Phoenician letter aleph , whic ...

, 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 labiod ...

, 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 fingers; pleckstrin homology (PH) domains; and domains similar to those in ubiquitin-conjugating (also known as E2) enzymes. Other UBDs not fitting these categories can be SH3 domains, 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 Motif may refer to: General concepts * Motif (chess composition), an element of a move in the consideration of its purpose * Motif (folkloristics), a recurring element that creates recognizable patterns in folklore and folk-art traditions * Moti ...

(MIU), and the VHS protein domain.

Binding mechanism

Many UBDs of the UBA family bind to ubiquitin via a hydrophobic patch centred on a particular

isoleucine Isoleucine (symbol Ile or I) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the deprot ...

residue (the "Ile44 patch"), although binding to other surface patches has been observed, for example the "Ile36 patch". Zinc finger 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 c ...

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

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