title: Selective Binding of AIRAPL Tandem UIMs to Lys48-Linked Tri-Ubiquitin Chains.
abstract: Lys48-linked ubiquitin chains act as the main targeting signals for protein degradation by the proteasome. Here we report selective binding of AIRAPL, a protein that associates with the proteasome upon exposure to arsenite, to Lys48-linked tri-ubiquitin chains. AIRAPL comprises two ubiquitin-interacting motifs in tandem (tUIMs) that are linked through a flexible inter-UIM region. In the complex crystal structure UIM1 binds the proximal ubiquitin, whereas UIM2 (the double-sided UIM) binds non-symmetrically to the middle and distal ubiquitin moieties on either side of the helix. Specificity of AIRAPL for Lys48-linked ubiquitin chains is determined by UIM2, and the flexible inter-UIM linker increases avidity by placing the two UIMs in an orientation that facilitates binding of the third ubiquitin to UIM1. Unlike middle and proximal ubiquitins, distal ubiquitin binds UIM2 through a novel surface, which leaves the Ile44 hydrophobic patch accessible for binding to the proteasomal ubiquitin receptors.
authors.affiliation: Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki 305-0801, Japan; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Simin
authors.initials: S
authors.lastname: Rahighi
authors.affiliation: Department of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Bat Galim, Haifa 31096, Israel.
authors.forename: Ilana
authors.initials: I
authors.lastname: Braunstein
authors.affiliation: TDI MS Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Ternette
authors.affiliation: TDI MS Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Kessler
authors.affiliation: Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki 305-0801, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kawasaki
authors.affiliation: Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki 305-0801, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Kato
authors.affiliation: Structural Molecular Biology, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Matsui
authors.affiliation: Structural Molecular Biology, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Weiss
authors.affiliation: Department of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Bat Galim, Haifa 31096, Israel. Electronic address: ariel.stanhill@gmail.com.
authors.forename: Ariel
authors.initials: A
authors.lastname: Stanhill
authors.affiliation: Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki 305-0801, Japan; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Structural Molecular Biology, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA; Photon Science, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA. Electronic address: soichi.wakatsuki@stanford.edu.
authors.forename: Soichi
authors.initials: S
authors.lastname: Wakatsuki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D025821:Polyubiquitin / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016601:RNA-Binding Proteins; C000607774:Zfand2b protein, mouse; D025821:Polyubiquitin; D008239:Lysine