title: The Functional Maturation of A Disintegrin and Metalloproteinase (ADAM) 9, 10, and 17 Requires Processing at a Newly Identified Proprotein Convertase (PC) Cleavage Site.
abstract: Proenzyme maturation is a general mechanism to control the activation of enzymes. Catalytically active members of the A Disintegrin And Metalloprotease (ADAM) family of membrane-anchored metalloproteases are synthesized as proenzymes, in which the latency is maintained by their autoinhibitory pro-domains. A proteolytic processing then transforms the proenzyme into a catalytically active form. The removal of the pro-domain of ADAMs is currently thought to depend on processing at a canonical consensus site for the proprotein convertase Furin (RXXR) between the pro- and the catalytic domain. Here, we demonstrate that this previously described canonical site is a secondary cleavage site to a prerequisite cleavage in a newly characterized upstream PC site embedded within the pro-domain sequence. The novel upstream regulatory site is important for the maturation of several ADAM proenzymes. Mutations in the upstream regulatory site of ADAM17, ADAM10, and ADAM9 do not prevent pro-domain processing between the pro- and metalloprotease domain, but nevertheless, cause significantly reduced catalytic activity. Thus, our results have uncovered a novel functionally relevant PC processing site in the N-terminal part of the pro-domain that is important for the activation of these ADAMs. These results suggest that the novel PC site is part of a general mechanism underlying proenzyme maturation of ADAMs that is independent of processing at the previously identified canonical Furin cleavage site.
authors: From the Department of Biological Regulation and.
authors: Eitan
authors: E
authors: Wong
authors: the Arthritis and Tissue Degeneration Program, Hospital for Special Surgery and.
authors: Thorsten
authors: T
authors: Maretzky
authors: The Israel Structural Proteomics Center, Weizmann Institute of Science, Rehovot, 7610001, Israel and.
authors: Yoav
authors: Y
authors: Peleg
authors: the Arthritis and Tissue Degeneration Program, Hospital for Special Surgery and the Departments of Medicine and of Physiology, Biophysics and Systems Biology, Weill Cornell Medical College, New York, New York 10021.
authors: Carl P
authors: CP
authors: Blobel
authors: From the Department of Biological Regulation and Irit.Sagi@weizmann.ac.il.
authors: Irit
authors: I
authors: Sagi
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002942:Circular Dichroism; D003001:Cloning, Molecular; D004926:Escherichia coli / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D045683:Furin / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000235:genetics; D017386:Sequence Homology, Amino Acid
chemical_list: D008565:Membrane Proteins; D011994:Recombinant Proteins; D053829:Amyloid Precursor Protein Secretases; D045683:Furin; D051722:ADAM Proteins; C498316:Adam9 protein, mouse; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse
keywords: ADAM; Epidermal Growth Factor Receptor (EGFR); Furin; Metalloprotease; Proenzyme Processing; Proprotein Convertase; Shedding