title: Metalloprotease meprin beta generates nontoxic N-terminal amyloid precursor protein fragments in vivo.
abstract: Identification of physiologically relevant substrates is still the most challenging part in protease research for understanding the biological activity of these enzymes. The zinc-dependent metalloprotease meprin β is known to be expressed in many tissues with functions in health and disease. Here, we demonstrate unique interactions between meprin β and the amyloid precursor protein (APP). Although APP is intensively studied as a ubiquitously expressed cell surface protein, which is involved in Alzheimer disease, its precise physiological role and relevance remain elusive. Based on a novel proteomics technique termed terminal amine isotopic labeling of substrates (TAILS), APP was identified as a substrate for meprin β. Processing of APP by meprin β was subsequently validated using in vitro and in vivo approaches. N-terminal APP fragments of about 11 and 20 kDa were found in human and mouse brain lysates but not in meprin β(-/-) mouse brain lysates. Although these APP fragments were in the range of those responsible for caspase-induced neurodegeneration, we did not detect cytotoxicity to primary neurons treated by these fragments. Our data demonstrate that meprin β is a physiologically relevant enzyme in APP processing.
authors.affiliation: Cell and Matrix Biology, Johannes Gutenberg-University, 55128 Mainz, Germany.
authors.forename: Tamara
authors.initials: T
authors.lastname: Jefferson
authors.forename: Mirsada
authors.initials: M
authors.lastname: Čaušević
authors.forename: Ulrich
authors.initials: U
authors.lastname: auf dem Keller
authors.forename: Oliver
authors.initials: O
authors.lastname: Schilling
authors.forename: Simone
authors.initials: S
authors.lastname: Isbert
authors.forename: Rebecca
authors.initials: R
authors.lastname: Geyer
authors.forename: Wladislaw
authors.initials: W
authors.lastname: Maier
authors.forename: Sabrina
authors.initials: S
authors.lastname: Tschickardt
authors.forename: Thorsten
authors.initials: T
authors.lastname: Jumpertz
authors.forename: Sascha
authors.initials: S
authors.lastname: Weggen
authors.forename: Judith S
authors.initials: JS
authors.lastname: Bond
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Overall
authors.forename: Claus U
authors.initials: CU
authors.lastname: Pietrzik
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker-Pauly
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000201:enzymology; D002460:Cell Line; D017931:DNA Primers; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D008625:Tiopronin / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D017931:DNA Primers; D020033:Protein Isoforms; D011994:Recombinant Proteins; D008625:Tiopronin