Ubiquitin-binding domain

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.^[2][3] Most UBDs bind to ubiquitin only weakly, with binding affinities in the low to mid μM range.^[4][5] Proteins containing UBDs are known as ubiquitin-binding proteins or sometimes as "ubiquitin receptors".^[2][4]

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, all-beta, 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); 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.^[5][6] Small helical structures are the most common, and examples include ubiquitin-associated domains (UBA), CUE domains, the ubiquitin-interacting motif (UIM), the motif interacting with ubiquitin (MIU), and the VHS protein domain.^[5]

Many UBDs of the UBA family bind to ubiquitin via a hydrophobic patch centred on a particular isoleucine residue (the "Ile44 patch"),^[7] although binding to other surface patches has been observed, for example the "Ile36 patch".^[8] Zinc finger UBDs have a broader range of binding modes including interactions with polar residues.^[5] Because many UBDs have a common or overlapping ubiquitin interaction surface, their interactions are often mutually exclusive; due to steric clashes, more than one UBD cannot physically interact with the same Ile44-centered hydrophobic patch on a single ubiquitin molecule.^[5]

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.^{[citation needed]}