Biomolecular Interaction of Matrix Metalloproteinases and Their Inhibitors TIMPs

Matrix metalloproteinases are a family of enzymes that altogether degrade almost all constituents of the extracellular matrix including collagens, laminin, elastin and fibronectin. Therefore, they are highly involved in the remodelling of the extracelluar matrix during embryogenesis, growth and development, and repair of tissues. Otherwise dysregulated proteolytic activity of matrix metalloproteinases is a key feature of a variety of diseases encompassing rheumatoid arthritis, multiple sclerosis, liver fibrosis, parodontosis, tumor formation and metastasis. In physiological processes the matrix metalloproteinases are precisely regulated by gene expression, secretion and activation of proenzymes and inhibition by their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). These proteins control the activation of the zymogens, especially of progelatinases, and the proteolytic activity of the mature enzymes. Besides ternary and quaternary complexes of gelatinases the typical complex between a matrix metalloproteinase and a TIMP is bimolecular and leads to a high affinity, quasi irreversible inhibition of the enzyme. Within the last few years several three-dimensional structures of MMPs and MMP-inhibitor complexes have been determined showing the polypeptide fold, domain organization, the architecture of the active site and binding modes of TIMPs and synthetic inhibitors. Based on these structural data enzyme kinetics and biomolecular analysis have clarified structure-funcion correlations of activation, proteolytic activity and inhibition by TIMPs.