title: Polyubiquitin substrates allosterically activate their own degradation by the 26S proteasome.
abstract: The 26S proteasome degrades polyubiquitylated (polyUb) proteins by an ATP-dependent mechanism. Here we show that binding of model polyUb substrates to the 19S regulator of mammalian and yeast 26S proteasomes enhances the peptidase activities of the 20S proteasome about two-fold in a process requiring ATP hydrolysis. Monoubiquitylated proteins or tetraubiquitin alone exert no effect. However, 26S proteasomes from the yeast alpha3DeltaN open-gate mutant and the rpt2YA and rpt5YA mutants with impaired gating can still be activated (approximately 1.3-fold to 1.8-fold) by polyUb-protein binding. Thus, binding of polyUb substrates to the 19S regulator stabilizes gate opening of the 20S proteasome and induces conformational changes of the 20S proteasome that facilitate channeling of substrates and their access to active sites. In consequence, polyUb substrates will allosterically stimulate their own degradation.
authors.affiliation: Institut für Biochemie, Charité-Universitätsmedizin Berlin, Monbijoustrasse 2, 10117 Berlin, Germany.
authors.forename: Dawadschargal
authors.initials: D
authors.lastname: Bech-Otschir
authors.forename: Annett
authors.initials: A
authors.lastname: Helfrich
authors.forename: Cordula
authors.initials: C
authors.lastname: Enenkel
authors.forename: Gesa
authors.initials: G
authors.lastname: Consiglieri
authors.forename: Michael
authors.initials: M
authors.lastname: Seeger
authors.forename: Hermann-Georg
authors.initials: HG
authors.lastname: Holzhütter
authors.forename: Burkhardt
authors.initials: B
authors.lastname: Dahlmann
authors.forename: Peter-Michael
authors.initials: PM
authors.lastname: Kloetzel
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D018396:Mucin-1 / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000378:metabolism
chemical_list: C060192:MUC1 protein, human; D018396:Mucin-1; D025821:Polyubiquitin; D046988:Proteasome Endopeptidase Complex