Ubiquitin-Dependent Protein Degradation

Abstract

A growing number of cellular regulatory mechanisms are being linked to protein modification by the polypeptide ubiquitin. These include key transitions in the cell cycle, class I antigen processing, signal transduction pathways, and receptor-mediated endocytosis. In most, but not all, of these examples, ubiquitination of a protein leads to its degradation by the 26S proteasome. Following attachment of ubiquitin to a substrate and binding of the ubiquitinated protein to the proteasome, the bound substrate must be unfolded (and eventually deubiquitinated) and translocated through a narrow set of channels that leads to the proteasome interior, where the polypeptide is cleaved into short peptides. Protein ubiquitination and deubiquitination are both mediated by large enzyme families, and the proteasome itself comprises a family of related but functionally distinct particles. This diversity underlies both the high substrate specificity of the ubiquitin system and the variety of regulatory mechanisms that it serves.

Identification of phosphatase 2A‐like Sit4‐mediated signalling and ubiquitin‐dependent protein sorting as modulators of caffeine sensitivity in S. cerevisiae

“…These include: its co-receptor Vps27 (Bilodeau et al, 2002); the E3 ubiquitin ligase Rsp5 and two of its regulatory partners, Rup1 and Bul1 (Belgareh-Touze et al, 2008;Kee et al, 2005); de-ubiquitinating peptidases, also referred to as DUbs [Upb2 and Ubp7 (Hochstrasser, 1996) (Ozkaynak et al, 1987)]. While a number of physical interactions link Rts3 to PP2A-related proteins (described above), genetic interactions also connect RTS3 to ubiquitin-dependent protein sorting.…”

The BMP signaling and in vivo bone formation

“…Smurf1 is a member of the Hect domain family of E3 ubiquitin ligases. Hect domain proteins represent a major subclass of E3 ligases and contain a conserved cysteine, located at the carboxyl terminal of the Hect domain, which is capable of forming a thioester bond with ubiquitin (Hochetrasser, 1996;Zhu et al, 1999). Mutation of this conserved cysteine residue to an alanine (C710A) abolished the ubiquitination and degradation activity of Smurf1 (Zhu et al, 1999).…”

Diverse splicing mechanisms fuse the evolutionarily conserved bicistronic MOCS1A and MOCS1B open reading frames

“…A second feature unique to the separate MOCS1A isoform produced by the bicistronic splice type is the invariant Gly-Gly dipeptide at its C-terminus (Figs+ 1, 2C)+ This distinctive feature may be significant, as a Gly-Gly dipeptide confers potent biological activity to the C-termini of other polypeptides, such as ubiquitin and ubiquitin-like proteins (Hochstrasser, 1996;Haas & Siepmann, 1997;Gray et al+, 1999)+ Any functional attributes specific to MOCS1A will only be revealed by future in vivo and in vitro analyses+ Nevertheless, it is evident that each MOCS1 splice form may encode proteins with distinct properties that would justify sustaining this gene structure and bimodal splice pattern over 700 million years+ Furthermore, the ratio of transcripts producing fused or separate polypeptides could differ during development or with environmental/dietary stimuli (Unkles et al+, 1997), consistent with our initial mouse studies suggesting tissue specificity+…”