title: Systematic substrate identification indicates a central role for the metalloprotease ADAM10 in axon targeting and synapse function.
abstract: Metzincin metalloproteases have major roles in intercellular communication by modulating the function of membrane proteins. One of the proteases is the a-disintegrin-and-metalloprotease 10 (ADAM10) which acts as alpha-secretase of the Alzheimer's disease amyloid precursor protein. ADAM10 is also required for neuronal network functions in murine brain, but neuronal ADAM10 substrates are only partly known. With a proteomic analysis of Adam10-deficient neurons we identified 91, mostly novel ADAM10 substrate candidates, making ADAM10 a major protease for membrane proteins in the nervous system. Several novel substrates, including the neuronal cell adhesion protein NrCAM, are involved in brain development. Indeed, we detected mistargeted axons in the olfactory bulb of conditional ADAM10-/- mice, which correlate with reduced cleavage of NrCAM, NCAM and other ADAM10 substrates. In summary, the novel ADAM10 substrates provide a molecular basis for neuronal network dysfunctions in conditional ADAM10-/- mice and demonstrate a fundamental function of ADAM10 in the brain.
authors.affiliation: Neuroproteomics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.|Institut für Pathologie und Pathologische Anatomie, Technische Universität München, Munich, Germany.|Institute for Advanced Study, Technische Universität München, Munich, Germany.
authors.forename: Peer-Hendrik
authors.identifier: http://orcid.org/0000-0001-7891-5102
authors.initials: PH
authors.lastname: Kuhn
authors.affiliation: Neuroproteomics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.|Deutsches Zentrum für Neurodegenerative Erkrankungen, Munich, Germany.
authors.forename: Alessio Vittorio
authors.initials: AV
authors.lastname: Colombo
authors.affiliation: Department of Animal Science, Institute for Animal Physiology, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schusser
authors.affiliation: Institute of Pharmacology and Toxicology, Uniklinik RWTH Aachen, Aachen, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Dreymueller
authors.affiliation: Institute of Biochemistry, Christian-Albrechts Universität zu Kiel, Kiel, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wetzel
authors.affiliation: Karlsruhe Institute of Technology, Karlsruhe, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Schepers
authors.affiliation: Neuroproteomics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.|Deutsches Zentrum für Neurodegenerative Erkrankungen, Munich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Herber
authors.affiliation: Institute of Pharmacology and Toxicology, Uniklinik RWTH Aachen, Aachen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ludwig
authors.affiliation: German Research Center for Environmental Health, Institute of Molecular Tumor immunology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.affiliation: Neurogenetics, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Dirk
authors.identifier: http://orcid.org/0000-0002-4964-1330
authors.initials: D
authors.lastname: Montag
authors.affiliation: Department of Functional Genomics, Institute for Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Müller
authors.affiliation: Service-Gruppe für Elektronenmikroskopie, Zentrum für Molekulare Neurobiologie, Hamburg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schweizer
authors.affiliation: Institute of Biochemistry, Christian-Albrechts Universität zu Kiel, Kiel, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.affiliation: Karlsruhe Institute of Technology, Karlsruhe, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bräse
authors.affiliation: Neuroproteomics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.|Institute for Advanced Study, Technische Universität München, Munich, Germany.|Deutsches Zentrum für Neurodegenerative Erkrankungen, Munich, Germany.|Munich Cluster for Systems Neurology, Munich, Germany.
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Lichtenthaler
mesh_terms: D000072197:ADAM10 Protein / Q000172:deficiency / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000737:chemistry / Q000201:enzymology*; D001921:Brain / Q000196:embryology / Q000201:enzymology; D055785:Gene Knockdown Techniques; D055786:Gene Knockout Techniques; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D020543:Proteome / Q000032:analysis; D013379:Substrate Specificity; D013569:Synapses / Q000201:enzymology*
chemical_list: D008565:Membrane Proteins; D020543:Proteome; D053829:Amyloid Precursor Protein Secretases; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse
keywords: <i>e. coli</i>; ADAM; alzheimer; bioorthogonal chemistry; cell biology; human; mass spectrometry; metalloproteases; mouse; neuroscience; rat