Activation mechanisms of the precursors of matrix metalloproteinases 1, 2 and 3

H Nagase, K Suzuki, T Morodomi, J J Enghild, G Salvesen

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    Abstract

    The zymogens of matrix metalloproteinase 1 (MMP-1: tissue collagenase), MMP-2 (gelatinase/type IV collagenase) and MMP-3 (stromelysin) were purified from the culture medium of human rheumatoid synovial fibroblasts and the mechanisms of activation of each zymogen by proteinases and 4-aminophenylmercuric acetate (APMA) were studied by kinetic and sequence analyses. The treatment of proMMP-1 (M(r) = 52,000) with proteinases or APMA converted the zymogen to M(r) = 43,000, but it exhibited only 14-25% of the maximal activity. Incubation of a partially active MMP-1 with MMP-3 resulted in rapid, full activation by generating the 41,000-M(r) MMP-1 with Phe81 as the NH2-terminus. MMP-3 directly activated proMMP-1 by cleaving the Gln80-Phe81 bond, but this reaction was extremely slow, indicating that the Gln80-Phe81 bond is not readily available to MMP-3 in the native proMMP-1 molecule. ProMMP-2 (M(r) = 72,000) was activated only by APMA, but not by proteinases. The activation by APMA was rapid and generated an active MMP-2 of M(r) 68,000, but the enzymic activity declined rapidly after activation by autolysis. The NH2-terminal sequence analysis of active MMP-2 indicated that the Asn80-Tyr81 bond was cleaved upon APMA treatment. In contrast, proMMP-3 (M(r) = 57,000) was activated by a variety of proteinases with different specificities. The initial attacks of these proteinases are on a stretch of highly charged groups at the position 34-39 in the propeptide.(ABSTRACT TRUNCATED AT 250 WORDS)
    Original languageEnglish
    JournalMatrix (Stuttgart, Germany). Supplement
    Volume1
    Pages (from-to)237-44
    Number of pages7
    ISSN0940-1199
    Publication statusPublished - 1992

    Keywords

    • Amino Acid Sequence
    • Arthritis, Rheumatoid
    • Collagenases
    • Endopeptidases
    • Enzyme Activation
    • Enzyme Precursors
    • Fibroblasts
    • Humans
    • Matrix Metalloproteinase 1
    • Matrix Metalloproteinase 2
    • Matrix Metalloproteinase 9
    • Metalloendopeptidases
    • Molecular Sequence Data
    • Molecular Weight
    • Phenylmercuric Acetate
    • Sequence Alignment
    • Synovial Fluid

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