A Disintegrin and Metalloproteinase with Thrombospondin Motifs-5 (ADAMTS-5) Forms Catalytically Active Oligomers.

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  • Additional Information
    • Source:
      Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
    • Publication Information:
      Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
      Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
    • Subject Terms:
      ADAM Proteins/*metabolism ; Aggrecans/*metabolism ; Arthritis, Experimental/*enzymology ; Knee Joint/*enzymology; ADAM Proteins/chemistry ; ADAM Proteins/genetics ; ADAM Proteins/isolation & purification ; ADAMTS5 Protein ; Aggrecans/isolation & purification ; Animals ; Arthritis, Experimental/immunology ; Arthritis, Experimental/pathology ; Catalytic Domain ; Cross-Linking Reagents/chemistry ; Crosses, Genetic ; Dimerization ; Enzyme Activation ; Gene Deletion ; HEK293 Cells ; Humans ; Knee Joint/immunology ; Knee Joint/pathology ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Molecular Weight ; Mutant Proteins ; Peptide Fragments/chemistry ; Peptide Fragments/genetics ; Peptide Fragments/isolation & purification ; Peptide Fragments/metabolism ; Protein Interaction Domains and Motifs ; Proteolysis ; Recombinant Fusion Proteins/chemistry ; Recombinant Fusion Proteins/isolation & purification ; Recombinant Fusion Proteins/metabolism
    • Abstract:
      The metalloproteinase ADAMTS-5 (A disintegrin and metalloproteinase with thrombospondin motifs) degrades aggrecan, a proteoglycan essential for cartilage structure and function. ADAMTS-5 is the major aggrecanase in mouse cartilage, and is also likely to be the major aggrecanase in humans. ADAMTS-5 is a multidomain enzyme, but the function of the C-terminal ancillary domains is poorly understood. We show that mutant ADAMTS-5 lacking the catalytic domain, but with a full suite of ancillary domains inhibits wild type ADAMTS activity, in vitro and in vivo, in a dominant-negative manner. The data suggest that mutant ADAMTS-5 binds to wild type ADAMTS-5; thus we tested the hypothesis that ADAMTS-5 associates to form oligomers. Co-elution, competition, and in situ PLA experiments using full-length and truncated recombinant ADAMTS-5 confirmed that ADAMTS-5 molecules interact, and showed that the catalytic and disintegrin-like domains support these intermolecular interactions. Cross-linking experiments revealed that recombinant ADAMTS-5 formed large, reduction-sensitive oligomers with a nominal molecular mass of ∼ 400 kDa. The oligomers were unimolecular and proteolytically active. ADAMTS-5 truncates comprising the disintegrin and/or catalytic domains were able to competitively block full-length ADAMTS-5-mediated aggrecan cleavage, measured by production of the G1-EGE(373) neoepitope. These results show that ADAMTS-5 oligomerization is required for full aggrecanase activity, and they provide evidence that blocking oligomerization inhibits ADAMTS-5 activity. The data identify the surface provided by the catalytic and disintegrin-like domains of ADAMTS-5 as a legitimate target for the design of aggrecanase inhibitors.
      (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)
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    • Contributed Indexing:
      Keywords: ADAMTS; ADAMTS5; aggrecan; cartilage; cartilage biology; metalloprotease; oligomer; oligomerization
    • Accession Number:
      0 (Acan protein, mouse)
      0 (Aggrecans)
      0 (Cross-Linking Reagents)
      0 (Mutant Proteins)
      0 (Peptide Fragments)
      0 (Recombinant Fusion Proteins)
      EC 3.4.24.- (ADAM Proteins)
      EC 3.4.24.- (ADAMTS5 Protein)
      EC 3.4.24.- (ADAMTS5 protein, human)
      EC 3.4.24.- (Adamts5 protein, mouse)
    • Publication Date:
      Date Created: 20151216 Date Completed: 20160706 Latest Revision: 20210205
    • Publication Date:
      20250114
    • Accession Number:
      PMC4751368
    • Accession Number:
      10.1074/jbc.M115.704817
    • Accession Number:
      26668318