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Description

Ubiquitin (Ub) is initially produced as a 229 amino acids Polyubiquitin-B (UniProt: P0CG47) precursor protein encoded by the UBB gene (Gene ID: 7314) or a 685 amino acids Polyubiquitin-C precursor protein (UniProt: P0CG48) encoded by the UBC gene (Gene ID: 7316) in human. Ub exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Ub is linked covalently via its carboxyl terminus (Gly76) to usually Lys residues in target proteins. In a given target Lys residue can be linked to one single Ub molecule (monoubiquitylated) or to a chain of Ub molecules (polyubiquitylated). In a polyUb chain, Ub molecules can be linked through one of the seven Lys residues (K6, K11, K27, K29, K33, K48, and K63) or through the Ub N-terminus Met1 residue (which generates linear chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked. For example, lysine 6-linked may be involved in DNA repair, lysine 11-linked is involved in endoplasmic reticulum-associated degradation (ERAD) and in cell-cycle regulation, and lysine 29-linked is involved in lysosomal degradation. Lysine 48-linked chains mark proteins for proteasomal degradation, while lysine 63-linked chains are involved in endocytosis, DNA-damage responses, and in signaling leading to activation of the transcription factor NF-kappa-B. Ubiquitin undergoes phosphorylation at the serine 57 by a ubiquitin kinase and this phosphorylation is an important modifier of ubiquitin function, particularly in response to proteotoxic stress. This phosphorylation may also be a deciding factor whether ubiquitin is recycled or degraded during multi-vesicular body sorting on endosomes. (Ref.: Hepowit, NL., et al (2020). eLife 9, e58155, Lee, S., et al. (2017) eLife. 6, e29176).