title: ADAMDEC1 is a metzincin metalloprotease with dampened proteolytic activity.
abstract: ADAMDEC1 (Decysin-1) is a putative ADAM (a disintegrin and metalloprotease)-like metalloprotease with an unknown physiological role, selectively expressed in mature dendritic cells and macrophages. When compared with other members of the ADAM family, ADAMDEC1 displays some unusual features. It lacks the auxiliary cysteine-rich, EGF, and transmembrane domains, as well as the cytoplasmic tail. The active site of ADAMDEC1 is unique by being the only mammalian ADAM protease with a non-histidine zinc ligand, having an aspartic acid residue instead. Here we demonstrate that ADAMDEC1, despite these unique features, functions as an active metalloprotease. Thus, ADAMDEC1 is secreted as a mature, glycosylated, and proteolytically active metalloprotease, capable of cleaving macromolecular substrates. In the recombinant form, three of the four potential N-linked glycosylation sites are modified by carbohydrate attachment. Substitution of basic residues at the predicted proprotein convertase cleavage site blocks proprotein processing, revealing both specific ADAMDEC1-dependent and specific ADAMDEC1-independent cleavage of the prodomain. The pro-form of ADAMDEC1 does not have proteolytic activity, demonstrating that the prodomain of ADAMDEC1, like in other members of the ADAM family, confers catalytic latency. Interestingly, the proteolytic activity of mature ADAMDEC1 can be significantly enhanced when a canonical ADAM active site with three zinc-coordinating histidine residues is introduced.
authors.affiliation: From the Department of Chemistry and Biotechnology, Aalborg University, DK-9000 Aalborg,; the Department of Haemophilia Biochemistry, Novo Nordisk A/S, DK-2760 Maaloev, and.
authors.forename: Jacob
authors.initials: J
authors.lastname: Lund
authors.affiliation: the Department of Haemophilia Biochemistry, Novo Nordisk A/S, DK-2760 Maaloev, and.
authors.forename: Ole H
authors.initials: OH
authors.lastname: Olsen
authors.affiliation: the Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus, Denmark.
authors.forename: Esben S
authors.initials: ES
authors.lastname: Sørensen
authors.affiliation: the Department of Haemophilia Biochemistry, Novo Nordisk A/S, DK-2760 Maaloev, and.
authors.forename: Henning R
authors.initials: HR
authors.lastname: Stennicke
authors.affiliation: the Department of Haemophilia Biochemistry, Novo Nordisk A/S, DK-2760 Maaloev, and.
authors.forename: Helle H
authors.initials: HH
authors.lastname: Petersen
authors.affiliation: From the Department of Chemistry and Biotechnology, Aalborg University, DK-9000 Aalborg,. Electronic address: mto@bio.aau.dk.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Overgaard
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry / Q000378:metabolism*; D055162:Biocatalysis; D006031:Glycosylation; D057809:HEK293 Cells; D006801:Humans; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D011994:Recombinant Proteins / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; D011994:Recombinant Proteins; D051722:ADAM Proteins; C108169:decysin; D015032:Zinc
keywords: ADAM ADAMTS; Metalloprotease; Metzincin; Post-translational Modification; Protein Evolution; Protein Expression