title: The Proteasome Distinguishes between Heterotypic and Homotypic Lysine-11-Linked Polyubiquitin Chains.
abstract: Proteasome-mediated degradation occurs with proteins principally modified with lysine-48 polyubiquitin chains. Whether the proteasome also can bind atypical ubiquitin chains, including those linked by lysine-11, has not been well established. This is critically important, as lysine-11 polyubiquitination has been implicated in both proteasome-mediated degradation and non-degradative outcomes. Here we demonstrate that pure homotypic lysine-11-linked chains do not bind strongly to the mammalian proteasome. By contrast, heterotypic polyubiquitin chains, containing lysine-11 and lysine-48 linkages, not only bind to the proteasome but also stimulate the proteasomal degradation of the cell-cycle regulator cyclin B1. Thus, while heterotypic lysine-11-linked chains facilitate proteasomal degradation, homotypic lysine-11 linkages adopt conformations that prevent association with the proteasome. Our data demonstrate the capacity of the proteasome to bind ubiquitin chains of distinct topology, with implications for the recognition and diverse biological functions of mixed ubiquitin chains.
authors.affiliation: Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge Biomedical Research Centre, Cambridge CB2 0XY, UK.
authors.forename: Guinevere L
authors.initials: GL
authors.lastname: Grice
authors.affiliation: Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge Biomedical Research Centre, Cambridge CB2 0XY, UK.
authors.forename: Ian T
authors.initials: IT
authors.lastname: Lobb
authors.affiliation: Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge Biomedical Research Centre, Cambridge CB2 0XY, UK; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Weekes
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge Biomedical Research Centre, Cambridge CB2 0XY, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Antrobus
authors.affiliation: Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge Biomedical Research Centre, Cambridge CB2 0XY, UK. Electronic address: jan33@cam.ac.uk.
authors.forename: James A
authors.initials: JA
authors.lastname: Nathan
mesh_terms: D000595:Amino Acid Sequence; D056744:Cyclin B1 / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008239:Lysine / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D025821:Polyubiquitin / Q000737:chemistry / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D059748:Proteolysis; D013379:Substrate Specificity; D054875:Ubiquitination
chemical_list: D056744:Cyclin B1; D025821:Polyubiquitin; D046988:Proteasome Endopeptidase Complex; D008239:Lysine