title: Metalloprotease meprin β is activated by transmembrane serine protease matriptase-2 at the cell surface thereby enhancing APP shedding.
abstract: Increased expression of metalloprotease meprin β is associated with fibrotic syndromes and Alzheimer's disease (AD). Hence, regulation of meprin activity might be a suitable strategy for the treatment of these conditions. Meprin β is a type 1 transmembrane protein, but can be released from the cell surface by ectodomain shedding. The protease is expressed as an inactive zymogen and requires proteolytic maturation by tryptic serine proteases. In the present study, we demonstrate, for the first time, the differences in the activation of soluble and membrane bound meprin β and suggest transmembrane serine protease 6 [TMPRSS6 or matriptase-2 (MT2)] as a new potent activator, cleaving off the propeptide of meprin β between Arg(61) and Asn(62) as determined by MS. We show that MT2, but not TMPRSS4 or pancreatic trypsin, is capable of activating full-length meprin β at the cell surface, analysed by specific fluorogenic peptide cleavage assay, Western blotting and confocal laser scanning microscopy (CLSM). Maturation of full-length meprin β is required for its activity as a cell surface sheddase, releasing the ectodomains of transmembrane proteins, as previously shown for the amyloid precursor protein (APP).
authors.affiliation: Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Jäckle
authors.affiliation: Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany.
authors.forename: Frederike
authors.initials: F
authors.lastname: Schmidt
authors.affiliation: Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany.
authors.forename: Rielana
authors.initials: R
authors.lastname: Wichert
authors.affiliation: Anatomical Institute, University of Kiel, 24118 Kiel, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Arnold
authors.affiliation: Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Prox
authors.affiliation: Pharmaceutical Institute, University of Bonn, 53121 Bonn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Mangold
authors.affiliation: Institute of Pathobiochemistry, University Medical Centre of the Johannes Gutenberg University of Mainz, 55128 Mainz, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Ohler
authors.affiliation: Institute of Pathobiochemistry, University Medical Centre of the Johannes Gutenberg University of Mainz, 55128 Mainz, Germany.
authors.forename: Claus U
authors.initials: CU
authors.lastname: Pietrzik
authors.affiliation: Institute of Experimental Medicine, University of Kiel, 24118 Kiel, Germany.
authors.forename: Tomas
authors.initials: T
authors.lastname: Koudelka
authors.affiliation: Institute of Experimental Medicine, University of Kiel, 24118 Kiel, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Tholey
authors.affiliation: Pharmaceutical Institute, University of Bonn, 53121 Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
authors.affiliation: Pharmaceutical Institute, University of Bonn, 53121 Bonn, Germany.
authors.forename: Marit
authors.initials: M
authors.lastname: Stirnberg
authors.affiliation: Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany cbeckerpauly@biochem.uni-kiel.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker-Pauly
mesh_terms: D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism*; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006801:Humans; D008666:Metalloendopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013552:Swine
chemical_list: D016564:Amyloid beta-Protein Precursor; D008666:Metalloendopeptidases; D012697:Serine Endopeptidases; C053833:meprin A; C421305:TMPRSS2 protein, human
keywords: amyloid precursor protein; cell membrane; enzymology; matriptase-2; meprin β; sheddase