Structural and Biochemical Basis for Higher-Order Assembly between A20-Binding Inhibitor of NF-κB 1 (ABIN1) and M1-Linked Ubiquitins |
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| Institution: | 1. Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan;2. Genomics Research Center, Academia Sinica, Taipei, Taiwan;3. Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 70101, Taiwan;1. MRC Protein Phosphorylation and Ubiquitylation Unit, Sir James Black Centre, Dow Street, Dundee, Scotland DD1 5EH, UK;2. Discovery, Janssen Research and Development, Welsh and McKean Roads, Spring House, PA 19477, USA;1. School of Biological Sciences and Institute of Microbiology, Seoul National University, Seoul 08826, South Korea;2. Biozentrum, University of Basel, Basel, Switzerland;1. Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), KAIST Institute of BioCentury, Daejeon 34141, Korea;2. Department of Physics and Astronomy, Institute of Applied Physics, Seoul National University, Seoul 08826, Korea;3. School of Engineering Sciences in Chemistry, Biotechnology and Health, Department of Biomedical Engineering and Health Systems, KTH Royal Institute of Technology, S-141 52 Huddinge, Sweden;4. Institut für Molekularbiologie und Tumorforschung (IMT), Biomedizinisches Forschungszentrum, Philipps-Universität Marburg, Marburg 35043, Germany;1. Department of Structural Biology, St. Jude Children''s Research Hospital, Memphis, TN 38105, USA;2. Department of Developmental Neurobiology, St. Jude Children''s Research Hospital, Memphis, TN 38105, USA;3. Present address: Sanofi, Waltham, MA 02451, USA;4. Department of Chemical Biology and Therapeutics, St. Jude Children''s Research Hospital, Memphis, TN 38105, USA;5. Molecular Interactions Analysis Shared Resource, St. Jude Children''s Research Hospital, Memphis, TN 38105, USA;6. Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE 68178, USA;7. Department of Microbiology, Immunology and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN 38163, USA;1. European Molecular Biology Laboratory, Structural and Computation Biology Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany;2. Molecular Cancer Research Group, Institute of Medical Biology, University of Tromsø – The Arctic University of Norway, 9037 Tromsø, Norway;1. Global Chemistry, UCB Biopharma UK, Slough SL1 3WE, UK;2. Protein Structure & Biophysics, UCB Biopharma UK, Slough SL1 3WE, UK;3. Biotech Sciences, UCB Biopharma UK, Slough SL1 3WE, UK;4. Immuno-Bone Discovery, UCB Biopharma UK, Slough SL1 3WE, UK;5. Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Technische Universiteit Eindhoven, Eindhoven 5600 MB, the Netherlands;6. Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Prague 12843, Czech Republic;7. Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX, USA;8. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA;9. Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA;10. Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA |
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| Abstract: | Polyubiquitination is important in controlling NF-κB signaling. Excessive NF-κB activity has been linked to inflammatory disorders and autoimmune diseases, while ABIN1 could attenuate NF-κB activation to maintain immune homeostasis by utilizing UBAN to recognize linear (M1)-linked polyubiquitinated NF-κB activation mediators, including NEMO, IRAK1 and RIP1. PolyUb-mediated UBAN recruitment remains undetermined, since the recognition studies focused mostly on di-ubiquitin (diUb). Here we report three crystal structures of human ABIN1 UBAN (hABIN1UBAN) in complex with M1-linked diUb, triUb, and tetraUb, respectively. Notably, the hABIN1UBAN:diUb structure reveals that a diUb randomly binds one of the Ub-binding sites of the hABIN1UBAN dimer and leaves the other site vacant. Together with the ITC and gel-filtration analyses, we found that M1-triUb and M1-tetraUb adopt two unique conformations, instead of an elongated one, and they preferentially use the N-terminal two-Ub unit to bind the primary Ub-binding site of a hABIN1UBAN dimer and the C-terminal two-Ub unit to bind the secondary Ub-binding site of another hABIN1UBAN dimer. Especially, our results suggest that two ABIN1UBAN dimers cooperatively bind two UBAN-binding units of a tetraUb or vice versa. Since the UBAN family members share a conserved diUb-binding mode, our results suggest that M1-polyUb modification allows multiple copies of the two-tandem Ub unit to simultaneously coordinate multiple and/or different binding partners to increase their local concentrations and to facilitate the formation of a large signaling complex. Our study provides a structural-functional glimpse of M1-polyUb as a multiple-molecule binding platform to exert its intrinsic structural plasticity in mediating cellular signaling. |
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| Keywords: | UBAN NF-κB signaling M1-linked ubiquitins signaling protein complex ABIN1 |
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