Internal Cleavages of the Autoinhibitory Prodomain Are Required for Membrane Type 1 Matrix Metalloproteinase Activation, although Furin Cleavage Alone Generates Inactive Proteinase
| Autor: | Alex Y. Strongin, Ilian A. Radichev, Boris I. Ratnikov, Alexei V. Chekanov, Dmitri V. Rozanov, Vladislav S. Golubkov, Tatiana I. Postnova, Natalya V. Golubkova, Alexander E. Aleshin, Wenhong Zhu, Khatereh Motamedchaboki, Piotr Cieplak |
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| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Proteolysis Molecular Sequence Data macromolecular substances Matrix Metalloproteinase Inhibitors Protein degradation Matrix metalloproteinase Cleavage (embryo) Biochemistry Enzyme activator stomatognathic system Cell Line Tumor Zymogen Matrix Metalloproteinase 14 medicine Animals Humans Amino Acid Sequence Molecular Biology Furin Peptide sequence Enzyme Precursors biology medicine.diagnostic_test Molecular Bases of Disease Cell Biology Protein Structure Tertiary Enzyme Activation Mutagenesis embryonic structures biology.protein |
| Zdroj: | Journal of Biological Chemistry. 285:27726-27736 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m110.135442 |
| Popis: | The functional activity of invasion-promoting membrane type 1 matrix metalloproteinase (MT1-MMP) is elevated in cancer. This elevated activity promotes cancer cell migration, invasion, and metastasis. MT1-MMP is synthesized as a zymogen, the latency of which is maintained by its prodomain. Excision by furin was considered sufficient for the prodomain release and MT1-MMP activation. We determined, however, that the full-length intact prodomain released by furin alone is a potent autoinhibitor of MT1-MMP. Additional MMP cleavages within the prodomain sequence are required to release the MT1-MMP enzyme activity. Using mutagenesis of the prodomain sequence and mass spectrometry analysis of the prodomain fragments, we demonstrated that the intradomain cleavage of the PGD/L(50) site initiates the MT1-MMP activation, whereas the (108)RRKR(111)/Y(112) cleavage by furin completes the removal and the degradation of the autoinhibitory prodomain and the liberation of the functional activity of the emerging enzyme of MT1-MMP. |
| Databáze: | OpenAIRE |
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