T

Transmembrane domain

Figure 5. Structure of the matrix metalloproteinase. MMPs contain the following domains: signal peptide (pre-pep-tide), propeptide, catalytic domain, hinge region, and hemopexin-like domain. The cleavage of N-terminal propeptide domain of the latent MMP yields the active form of the enzyme. The gelatinases contain a fibronectin-like region within their catalytic domain. The membrane-type MMPs are characterised by a C-terminal transmembrane domain. The hemopexin-like repeat is absent in matrilysin (MMP-7).

Common names are also used to distinguish substrate specificity for each of the MMP groups described above. For example, interstitial collagenases, such as MMP-1 (structural group 2), have high specificity for fibrillar collagen types I, II, and III. In contrast, gelatinases, MMP-2 and MMP-9 (structural group 3), have a greater propensity to cleave denatured collagen products, as well as basement membrane components such as collagen type IV. Stromelysins, such as MMP-3 (structural group 2), cleave extracellular components and have the ability to activate other MMPs. Recently, a new subfamily of membrane-tethered or membrane-type MMPs, MT-MMPs (Group 6) has been included in the MMP family. Five enzymes: MT1-, MT2-, MT3-, MT4- and MT5- (Sato et al., 1996; Takino et al., 1995; Will and Hinzmann, 1995; Puente et al., 1996; Pei, 1999) have been identified as members of this group.

MMPs are synthesized as inactive zymogen requiring proteolytic cleavage of the N-termi-nus in order to be activated. A cysteine-sulphydryl group in the propeptide domain interacts with a zinc ion bound to the catalytic domain. Proteolytic cleavage removes the propeptide domain, leading to the activation of latent MMP (Cao et al., 1998). Generally, MMPs are activated by either serine proteinases or other activated MMPs outside of the cell. In contrast, MMP-11, MMP-28 and MT-MMPs are activated by intracellular furin-like serine proteinases before they are associated with the cell membrane. MMP activity is regulated at three levels: transcription, activation, and inhibition/deactivation.

0 0

Post a comment