Rpn1 and Rpn2 coordinate ubiquitin processing factors at the proteasome

TitleRpn1 and Rpn2 coordinate ubiquitin processing factors at the proteasome
Publication TypeJournal Articles
Year of Publication2012
AuthorsRosenzweig R, Bronner V, Zhang D, Fushman D, Glickman MH
JournalJournal of Biological ChemistryJ. Biol. Chem.
Date Published2012/02/08/
ISBN Number0021-9258, 1083-351X
Keywordsdeubiquitination, Proteasome, solenoid, Surface plasmon resonance (SPR), ubiquitin, Ubiquitin-dependent protease

Substrates tagged with (poly)ubiquitin for degradation can be targeted directly to the 26S proteasome where they are proteolysed. Independently, ubiquitin-conjugates may also be delivered by bivalent shuttles. The majority of shuttles attach to the proteasome through a ubiquitin-like domain (UBL) while anchoring cargo at a C-terminal polyubiquitin-binding domain(s). We found that two shuttles of this class, Rad23 and Dsk2, dock at two different receptors embedded within a single subunit of the 19S proteasome regulatory particle (RP), Rpn1. Their association/dissociation constants and affinities for Rpn1 are similar. In contrast, another UBL-containing protein, the deubiquitinase Ubp6, is also anchored by Rpn1, yet dissociates slower, thus behaving as a sometimes proteasome subunit distinct from transiently-associated shuttles. Two neighboring subunits, Rpn10 and Rpn13, show a marked preference for polyubiquitin over UBLs. Rpn10 attaches to the central solenoid portion of Rpn1 although this association is stabilized by the presence of a third subunit, Rpn2. Rpn13 binds directly to the C-terminal portion of Rpn2. These intrinsic polyubiquitin receptors may compete with substrate shuttles for their polyubiquitin-conjugates, thereby aiding release of the emptied shuttles. By binding multiple ubiquitin-processing factors simultaneously, Rpn1 is uniquely suited to coordinate substrate recruitment, deubiquitination, and movement towards the catalytic core. The broad range of affinities for ubiquitin, ubiquitin-like, and non-ubiquitin signals by adjacent yet non-overlapping sites all within the Base illustrates a hub of activity that coordinates the intricate relay of substrates within the proteasome, and consequently influences substrate residency time and commitment to degradation.