title: Mechanisms of splicing-dependent trans-synaptic adhesion by PTPδ-IL1RAPL1/IL-1RAcP for synaptic differentiation.
abstract: Synapse formation is triggered through trans-synaptic interaction between pairs of pre- and postsynaptic adhesion molecules, the specificity of which depends on splice inserts known as 'splice-insert signaling codes'. Receptor protein tyrosine phosphatase δ (PTPδ) can bidirectionally induce pre- and postsynaptic differentiation of neurons by trans-synaptically binding to interleukin-1 receptor accessory protein (IL-1RAcP) and IL-1RAcP-like-1 (IL1RAPL1) in a splicing-dependent manner. Here, we report crystal structures of PTPδ in complex with IL1RAPL1 and IL-1RAcP. The first immunoglobulin-like (Ig) domain of IL1RAPL1 directly recognizes the first splice insert, which is critical for binding to IL1RAPL1. The second splice insert functions as an adjustable linker that positions the Ig2 and Ig3 domains of PTPδ for simultaneously interacting with the Ig1 domain of IL1RAPL1 or IL-1RAcP. We further identified the IL1RAPL1-specific interaction, which appears coupled to the first-splice-insert-mediated interaction. Our results thus reveal the decoding mechanism of splice-insert signaling codes for synaptic differentiation induced by trans-synaptic adhesion between PTPδ and IL1RAPL1/IL-1RAcP.
authors.affiliation: 1] Structural Biology Laboratory, Life Science Division, Synchrotron Radiation Research Organization and Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan [2] Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8501, Japan [3] CREST, JST, Saitama 332-0012, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamagata
authors.affiliation: 1] Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan [2] Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan [3] PRESTO, JST, Saitama 332-0012, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: 1] Structural Biology Laboratory, Life Science Division, Synchrotron Radiation Research Organization and Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan [2] Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8501, Japan [3] CREST, JST, Saitama 332-0012, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Structural Biology Laboratory, Life Science Division, Synchrotron Radiation Research Organization and Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
authors.forename: Sakurako
authors.initials: S
authors.lastname: Goto-Ito
authors.affiliation: 1] CREST, JST, Saitama 332-0012, Japan [2] Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan [3] Department of Molecular and Cellular Physiology, Shinshu University School of Medicine, Nagano 390-8621, Japan [4] Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Nagano 390-8621, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Uemura
authors.affiliation: 1] Structural Biology Laboratory, Life Science Division, Synchrotron Radiation Research Organization and Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan [2] CREST, JST, Saitama 332-0012, Japan.
authors.forename: Asami
authors.initials: A
authors.lastname: Maeda
authors.affiliation: 1] Structural Biology Laboratory, Life Science Division, Synchrotron Radiation Research Organization and Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan [2] CREST, JST, Saitama 332-0012, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Shiroshima
authors.affiliation: 1] Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan [2] PRESTO, JST, Saitama 332-0012, Japan.
authors.forename: Shiho
authors.initials: S
authors.lastname: Iwasawa-Okamoto
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Mori
authors.affiliation: 1] Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan [2] Brain Science Laboratory, The Research Organization of Science and Technology, Ritsumeikan University, Shiga 525-8577, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Mishina
authors.affiliation: 1] Structural Biology Laboratory, Life Science Division, Synchrotron Radiation Research Organization and Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan [2] Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8501, Japan [3] CREST, JST, Saitama 332-0012, Japan.
authors.forename: Shuya
authors.initials: S
authors.lastname: Fukai
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D018920:Coculture Techniques; D057809:HEK293 Cells; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism; D053577:Interleukin-1 Receptor Accessory Protein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D009474:Neurons / Q000502:physiology; D011487:Protein Conformation; D020033:Protein Isoforms; D012326:RNA Splicing / Q000502:physiology*; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000502:physiology*
chemical_list: C507767:Il1rap protein, mouse; D007136:Immunoglobulins; D053577:Interleukin-1 Receptor Accessory Protein; D020033:Protein Isoforms; C568303:interleukin-1 receptor accessory protein-like 1, mouse; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2