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Mutations in the Interglobular Domain of Aggrecan Alter Matrix Metalloproteinase and Aggrecanase Cleavage Patterns

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Mercuri, Francesca A., Maciewicz, Rose A., Tart, Jonathan, Last, Karena, Fosang, Amanda J.·2000·Journal of Biological Chemistry
DOI 10.1074/jbc.275.42.33038
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Abstract

We have expressed G1-G2 mutants with amino acid changes at the DIPEN(341) downward arrow(342)FFGVG and ITEGE(373) downward arrow(374)ARGSV cleavage sites, in order to investigate the relationship between matrix metalloproteinase (MMP) and aggrecanase activities in the interglobular domain (IGD) of aggrecan. The mutation DIPEN(341) to DIGSA(341) partially blocked cleavage by MMP-13 and MMP-8 at the MMP site, while the mutation (342)FFGVG to (342)GTRVG completely blocked cleavage at this site by MMP-1, -2, -3, -7, -8, -9, -13, -14. Each of the MMP cleavage site mutants, including a four-amino acid deletion mutant lacking residues ENFF(343), were efficiently cleaved by aggrecanase, suggesting that the primary sequence at the MMP site had no effect on aggrecanase activity in the IGD. The mutation (374)ARGSV to (374)NVYSV completely blocked cleavage at the aggrecanase site by aggrecanase, MMP-8 and atrolysin C but had no effect on the ability of MMP-8 and MMP-13 to cleave at the Asn(341) downward arrowPhe bond. Susceptibility to atrolysin C cleavage at the MMP site was conferred in the DIGSA(341) mutant but absent in the wild-type, (342)GTRVG, (374)NVYSV, and deletion mutants. To further explore the relationship between MMP and aggrecanase activities, sequential digest experiments were done in which MMP degradation products were subsequently digested with aggrecanase and vice versa. Aggrecanase-derived G1 domains with ITEGE(373) C termini were viable substrates for MMPs; however, MMP-derived G2 fragments were resistant to cleavage by aggrecanase. A 10-mer peptide FVDIPENFFG, which is a substrate analogue for the MMP cleavage site, inhibited aggrecanase cleavage at the Glu(373) downward arrowAla bond. This study demonstrates that MMPs and aggrecanase have unique substrate recognition in the IGD of aggrecan and suggests that sequences at the C terminus of the DIPEN(341) G1 domain may be important for regulating aggrecanase cleavage.

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  • Aggrecan has been previously identified as an MMP-9 target.

    “As aggrecan has been previously identified as an MMP-9 target (Mercuri et al., 2000; Madsen et al., 2010; Rankin-Gee et al., 2015), aggrecan-rich PNNs may be unstable in the presence of MMP-9, leading to abnormal development and neural excitability (Murase et al., 2017; Wen et al., 2017).”

    From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Mercuri et al., 2000

  • The increase in perisynaptic MMP activity induced by salient experience is associated with a specific class of synapse (thalamic inputs to cortex), and a decrease in aggrecan.

    “In addition, we show that the increase in perisynaptic MMP activity induced by salient experience is associated with a specific class of synapse (thalamic inputs to cortex), and a decrease in aggrecan, a known MMP-9 substrate (Mercuri et al., 2000).”

    From Light reintroduction after dark exposure reactivates plasticity in adults via perisynaptic activation of MMP-9 (2017) · cites this paper as Mercuri et al., 2000

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Authors
Mercuri, F. A., Maciewicz, R. A., Tart, J., Last, K., & Fosang, A. J.
Affiliations
  • Royal Children's Hospital (AU)
  • AstraZeneca (United Kingdom) (GB)
Corresponding author
Fosang, Amanda J.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2000-10
Volume
275
Issue
42
Pages
33038-33045
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.275.42.33038
OpenAlex
W2127183158
Cited by
52
References
55
Citations by year
2025: 2 · 2024: 1 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 1 · 2017: 1 · 2015: 3 · 2012: 1
FWCI
1.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
  • Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
Keywords
interglobular domain, matrix metalloproteinases, aggrecanase, substrate specificity, MMP-13, MMP-8, substrate analogues, proteolytic cleavage, proteoglycan degradation, cartilage proteolysis, chondroitin sulfate
MeSH terms
Amino Acid Sequence, Animals, Base Sequence, Binding Sites, Enzyme Precursors, Humans, Metalloendopeptidases, Molecular Sequence Data, Endopeptidases, Chondroitin Sulfate Proteoglycans, Proteoglycans, Recombinant Proteins, Substrate Specificity, Mutagenesis, Site-Directed, Extracellular Matrix Proteins, Collagenases, DNA Primers, Gelatinases, Spodoptera, Tissue Inhibitor of Metalloproteinase-1, Matrix Metalloproteinase 9, Matrix Metalloproteinase 1, Matrix Metalloproteinases, Lectins, C-Type, Aggrecans

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