The structure and function of MMP, ADAM and ADAMTS metalloproteinases
Principal investigator: Prof. Hideaki Nagase - h.nagase@imperial.ac.uk (personal page)
The main aims of our research are to investigate the structure and function of metalloproteinases that participate in the destruction of cartilage matrix in arthritis, and to engineer selective TIMPs that inhibit those destructive enzymes. We also investigate the role of metalloproteinases in the progression of osteoarthritis, a common age-related degenerative joint disease.
Current Interests:
- The mechanisms of action of collagenases on triple helical collagen.
- The function of non-catalytic domains of ADAMTS-4 and ADAMTS-5 in modulating substrate specificity.
- The engineering of TIMP variants for structural studies and their use as protectants of cartilage destruction.
- The induction of matrix breakdown by fibronectin fragments generated by proteolysis.
Reviews:
- Murphy, G. and H. Nagase (2008)
Reappraising metalloproteinases in rheumatoid arthritis and osteoarthritis: destruction or repair?.
Nat Clin Pract Rheumatol 4(3): 128-35. - Murphy, G. and H. Nagase (2008)
Progress in matrix metalloprotease research.
Mol. Asp. Med. 29(5) 290-308 - H. Nagase and Murphy, G. (2008)
Tailoring TIMPs for selective metalloproteinase inhibition.
In the Cancer Degradome. D. Edwards et al. (Eds.) Springer Science. pp
- Nagase, H., Visse, R., and Murphy, G. (2006)
Structure and function of matrix metalloproteinases and TIMPs.
Cardiovasc Res 69: 562-573
- Nagase, H., Murphy, G. (2004)
Metalloproteinases, Matrix.
Encyclopedia of Biological Chemistry. Elsevier, Oxford.
- Visse, R., Nagase, H. (2003)
Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry.
Circ Res. 92: 827-839
- Nagase, H., Brew, K. (2003)
Designing TIMP (tissue inhibitor of metalloproteinases) variants that are selective metalloproteinase inhibitors.
Biochem Soc Symp. 201-212
- Nagase, H., Kashiwagi, M. (2003)
Aggrecanases and cartilage matrix degradation.
Arthritis Res Ther. 5: 94-103
Book.
- Woessner, F. F., Nagase, H. (2000)
Matrix Metalloproteinases and TIMPs.
Oxford University Press
General References:
* Primary work conducted in department.
- *Troeberg L, Fushimi K, Khokha R, Emonard H, Ghosh P, and Nagase H. (2008)
Calcium pentosan polysulfate is a multi-faceted exosite inhibitor of aggecanases.
FASEB J.
[Abstract]
- *Fushimi, K., L. Troeberg, H. Nakamura, N. H. Lim and H. Nagase (2008)
Functional differences of the catalytic and non-catalytic domains in human ADAMTS-4 and ADAMTS-5 in aggrecanolytic activity.
J Biol Chem 283(11): 6706-16
[Abstract] - *Gendron, C., M. Kashiwagi, N. H. Lim, J. J. Enghild, I. B. Thogersen, C. Hughes, B. Caterson and H. Nagase (2007)
Proteolytic activities of human ADAMTS-5: comparative studies with ADAMTS-4.
J Biol Chem 282(25): 18294-306
[Abstract] - *Itoh, Y., N. Ito, H. Nagase and M. Seiki (2008)
The second dimer interface of MT1-MMP, the transmembrane domain, is essential for ProMMP-2 activation on the cell surface.
J Biol Chem 283(19): 13053-62
[Abstract] - *Jacobsen, J., R. Visse, H. P. Sorensen, J. J. Enghild, K. Brew, U. M. Wewer and H. Nagase (2008)
Catalytic properties of ADAM12 and its domain deletion mutants.
Biochemistry 47(2): 537-47
[Abstract] - Kopitz, C., M. Gerg, O. R. Bandapalli, D. Ister, C. J. Pennington, S. Hauser, C. Flechsig, H. W. Krell, D. Antolovic, K. Brew, H. Nagase, M. Stangl, C. W. von Weyhern, B. L. Brucher, K. Brand, L. M. Coussens, D. R. Edwards and A. Kruger (2007)
Tissue inhibitor of metalloproteinases-1 promotes liver metastasis by induction of hepatocyte growth factor signaling.
Cancer Res 67(18): 8615-23
[Abstract] - Lauer-Fields, J. L., D. Minond, T. Sritharan, M. Kashiwagi, H. Nagase and G. B. Fields (2007)
Substrate conformation modulates aggrecanase (ADAMTS-4) affinity and sequence specificity. Suggestion of a common topological specificity for functionally diverse proteases.
J Biol Chem 282(1): 142-50
[Abstract] - *Wei, S., Kashiwagi, M., Kota, S., Xie, Z., Nagase, H., Brew, K. (2005)
Reactive site mutations in tissue inhibitor of metalloproteinase-3 disrupt inhibition of matrix metalloproteinases but not tumor necrosis factor-alpha-converting enzyme.
J Biol Chem 280, 32877-82
[Astract]
- *Anilkumar, N., Uekita, T., Couchman, J. R., Nagase, H., Seiki, M., and Itoh, Y. (2005)
Palmitoylation at Cys574 is essential for MT1-MMP to promote cell migration.
Faseb J 19, 1326-1328
[Abstract]
- *Jozic, D., Bourenkov, G., Lim, N. H., Visse, R., Nagase, H., Bode, W., and Maskos, K. (2005)
X-ray structure of human proMMP-1: new insights into procollagenase activation and collagen binding.
J Biol Chem 280, 9578-9585.
[Abstract]
- Emonard, H., Bellon, G., Troeberg, L., Berton, A., Robinet, A., Henriet, P., Marbaix, E., Kirkegaard, K., Patthy, L., Eeckhout, Y., Nagase, H., Hornebeck, W., and Courtoy, P. J. (2004)
Low density lipoprotein receptor-related protein mediates endocytic clearance of pro-MMP-2.TIMP-2 complex through a thrombospondin-independent mechanism.
J Biol Chem 279, 54944-54951.
[Abstract]
- Minond, D., Lauer-Fields, J. L., Nagase, H., and Fields, G. B. (2004)
Matrix metalloproteinase triple-helical peptidase activities are differentially regulated by substrate stability.
Biochemistry 43, 11474-11481.
[Abstract]
- *Chung, L., Dinakarpandian, D., Yoshida, N., Lauer-Fields, J. L., Fields, G. B., Visse, R., and Nagase, H. (2004)
Collagenase unwinds triple-helical collagen prior to peptide bond hydrolysis.
Embo J 23, 3020-3030.
[Abstract]
- *Kashiwagi, M., Enghild, J. J., Gendron, C., Hughes, C., Caterson, B., Itoh, Y., and Nagase, H. (2004)
Altered proteolytic activities of ADAMTS-4 expressed by C-terminal processing.
J Biol Chem 279, 10109-10119.
[Abstract]
- *Gendron, C., Kashiwagi, M., Hughes, C., Caterson, B., and Nagase, H. (2003)
TIMP-3 inhibits aggrecanase-mediated glycosaminoglycan release from cartilage explants stimulated by catabolic factors.
FEBS Lett 555, 431-436
[Abstract]
- Ahonen, M., Poukkula, M., Baker, A. H., Kashiwagi, M., Nagase, H., Eriksson, J. E., and Kahari, V. M. (2003)
Tissue inhibitor of metalloproteinases-3 induces apoptosis in melanoma cells by stabilization of death receptors.
Oncogene 22, 2121-2134 - *Wei, S., Chen, Y., Chung, L., Nagase, H., and Brew, K. (2003)
Protein engineering of the tissue inhibitor of metalloproteinase 1 (TIMP-1) inhibitory domain. In search of selective matrix metalloproteinase inhibitors.
J Biol Chem 278, 9831-9834
[Abstract]
