Go Back MMP 14 (MT1-MMP) prodomain-catalytic domain

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Matrix metalloproteinases (MMPs) are Zn2+- and Ca2+-dependent endopeptidases which function in the turnover of extracellular matrix components [1]. Presently fifteen secreted MMPs and six membrane-type MMPs [2-5] are known to be expressed in humans. Human MT1-MMP consists of 559 amino acid residues with a calculated Mr of 63 516 Da [2, 3].

The following domains and sequence regions are distinguished in MT1-MMP: Prodomain (Ser1 - Arg88), catalytic domain (Tyr89 - Gly261), junction between catalytic domain and hemopexin domain (Gly262 - Gly292), hemopexin-like domain (Pro293 - Cys485) and C-terminal sequence (Pro486 - Val559) with transmembrane segment. A soluble form of MT1-MMP without transmembrane segment has been found in culture medium of a breast carcinoma cell line [6]. MT1-MMP is expressed in adult lung, placenta, kidney, ovaries, intestine, prostate and spleen [3]. Increased amounts of the enzyme are found in tumor tissues [2, 7, 8]. MT1-MMP is activated by removal of its prodomain. The reaction is catalyzed by furin, a subtilysin-type serine protease, which recognizes a motif of four basic amino acid residues located between prodomain and catalytic domain [9]. MT1-MMP activates progelatinase A (72-kDa type IV procollagenase) [2, 10, 11] and procollagenase-3 [12] by proteolytic cleavage of their prodomains. The ability of MT1-MMP to activate other matrix metalloproteinases provides potential for enhanced pericellular proteolysis in physiological and pathological processes. MT1-MMP hydrolyzes also fibrillar collagens I, II and III into characteristic ¾ and ¼ fragments [13] and it cleaves a number of other proteins of the extracellular matrix, among them fibronectin, vitronectin, laminin-1 and dermatan sulfate proteoglycan [6,13]. The activity of MT1-MMP is poorly inhibited by tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), but efficiently inhibited by TIMP-2 and TIMP-3 [11].