Matrix MetaIIoproteinase Substrate Binding Domains, Modules and Exosites: Overview and Experimental

Connective tissue degradation occurs in chronic inflammatory diseases such as arthritis and periodontitis to adversely affect life quality. More importantly, disturbances in connective tissue homeostasis may be life threatening in various lung, neurological, and cardiovascular diseases and is pivotal in tumor metastasis. Matrix metalloproteinases (MMPs) form one of the most important families of proteinases that participate in the degradative aspects of these diseases. The specific inhibition of MMPs by the four members of the tissue inhibitor of metalloproteinase (TIMP) family can regulate the extracellular activity of MMPs (1 ). Not surprisingly, altered TIMP expression is also known to occur in many disease processes. Activation of MMP zymogens is another critical aspect of the regulation of connective tissue matrix composition, structure, and function. For some soluble MMPs, activation occurs at the cell surface following proteolytic cleavage by membrane type MMPs (MT-MMPs), often in a TIMP-dependent pathway. For other MMPs, activation occurs in the extracellular environment in an activation cascade initiated by tissue proteinases, such as plasmin, kallikrein, and tryptase, a process that is often amplified by the activated MMPs themselves functioning as proMMP activators. Therefore, understanding the structural basis of MMP function, in particular substrate recognition and cleavage, MMP inhibition by TIMPs and synthetic inhibitors, and the domain:domain interactions that occur in the activation and association of MMPs and TIMPs with the cell membrane and in the matrix, may point to new avenues of therapeutic intervention or refine existing MMP inhibitor strategies.