Progress in matrix metalloproteinase research

Abstract

Matrix metalloproteinases (MMPs) are now acknowledged as key players in the regulation of both cell-cell and cell-extracellular matrix interactions. They are involved in modifying matrix structure, growth factor availability and the function of cell surface signalling systems, with consequent effects on cellular differentiation, proliferation and apoptosis. They play central roles in morphogenesis, wound healing, tissue repair and remodelling in response to injury and in the progression of diseases such as arthritis, cancer and cardiovascular disease. Because of their wide spectrum of activities and expression sites, the elucidation of their potential as drug targets in disease or as important features of the repair process will be dependent upon careful analysis of their role in different cellular locations and at different disease stages. Novel approaches to the specific regulation of individual MMPs in different contexts are also being developed.

Fig. 1

Domain structures of the matrixin family. See Table 1 for the domain arrangement of each MMP. ss, signal sequence; pro, pro-domain, FNII, fibronectin type II motif; L1, linker 1; L2, linker 2; Mb, plasma membrane; TM, transmembrane domain; CT, cytoplamic tail; CysR, cysteine rich; Ig, immunoglobulin domain; GPI, glycosylphosphatidylinositol anchor; C, cysteine.

Fig. 2

The three-dimensional diagram of human proMMP-2 and TIMP-2 complex. The pro-domain is shown in green, catalytic domain in red, fibronectin type II domains in blue, hemopexin domain in orange, and TIMP-2 in pink. Zinc ion is in green sphere, calcium ion in blue sphere and disulfide bonds in yellow. The image was prepared by Rob Visse of Imperial College London based on Brookhaven Protein Data Bank entry 1GXD.¹¹

Fig. 3

The three-dimensional diagram of TIMP-1 bound to the catalytic domain of MMP-3. (A) TIMP-1-MMP-3 complex. (B) The reactive centre residues of TIMP-1 in the active site of MMP-3. TIMP-1 is in red, MMP-3 is in blue. Disulfide bonds are shown in yellow, zinc ions in pink and calcium ions in blue. The image was prepared by Rob Visse of Imperial College London based on Brookhaven Protein Data Bank entry 1UEA.

Fig. 4

Superimposition of the N-terminal domains of TIMP-1 and TIMP-2. TIMP-1 is shown in blue and TIMP-2 in orange. The residues subjected to mutagenesis studies are illustrated and disulfide bonds are in yellow. The image was prepared by Rob Visse of Imperial College London based on Brookhaven Protein Data Bank entries 1UEA for TIMP-1 and IBQQ for TIMP-2.