Interaction of 92-kDa type IV collagenase with the tissue inhibitor of metalloproteinases prevents dimerization, complex formation with interstitial collagenase, and activation of the proenzyme with stromelysin.
Interaction of 92-kDa type IV collagenase with the tissue inhibitor of metalloproteinases prevents dimerization, complex formation with interstitial collagenase, and activation of the proenzyme with stromelysin.
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DOI：
10.1016/s0021-9258(18)42873-6
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发表时间：
1992-03
期刊：
影响因子：
--
通讯作者：
G. Goldberg;A. Strongin;I. Collier;L. T. Genrich;B. Marmer
中科院分区：
文献类型：
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作者：
G. Goldberg;A. Strongin;I. Collier;L. T. Genrich;B. Marmer
分泌的金属蛋白酶启动胶原蛋白和蛋白聚糖的蛋白水解降解，在结缔组织的重塑中起关键作用。分泌的酶原的激活及其与其特异性抑制剂TIMP和TIMP-2的相互作用负责调节细胞外空间中的酶活性。我们以前已经证明，92-和72-kDa的IV型前胶原酶，与间质胶原酶（ClI），形成特定的复合物与TIMP和相关的抑制剂TIMP-2，分别。酶原-抑制剂复合物的生理学意义和IV型胶原酶的激活机制尚不清楚。在这里，我们证明，在TIMP的情况下，92-kDa的IV型前胶原酶（92 T4 Cl）可以形成一个共价的同源二聚体和一个新的复合物与ClI。在TIMP存在下，与TIMP形成92 T4 Cl酶原复合物可防止二聚化、与ClI形成复合物以及92 T4 Cl酶原被基质分解素（一种相关的金属蛋白酶）激活。酶原同二聚体无法与TIMP形成复合物。所有不含TIMP的酶原形式都可以被基质分解素激活。92 T4 Cl-ClI复合物可被活化以产生对明胶和纤维状I型胶原蛋白两者都有活性的复合物，这表明在生理条件下两种酶在将胶原纤维还原成小肽中的协同作用的机制。
Secreted metalloproteases initiating proteolytic degradation of collagens and proteoglycans play a critical role in remodeling of the connective tissue. Activation of the secreted proenzymes and interaction with their specific inhibitors TIMP and TIMP-2 are responsible for regulation of enzyme activity in extracellular space. We have previously demonstrated that 92- and 72-kDa Type IV procollagenases, in contrast to interstitial collagenase (ClI), form specific complexes with TIMP and the related inhibitor TIMP-2, respectively. The physiologic significance of the proenzyme-inhibitor complex and the mechanism of activation of Type IV collagenases remained unclear. Here, we demonstrate that in the absence of TIMP, 92-kDa Type IV procollagenase (92T4Cl) can form a covalent homodimer and a novel complex with ClI. In the presence of TIMP, the formation of a 92T4Cl proenzyme complex with TIMP prevents dimerization, formation of the complex with ClI, and activation of the 92T4Cl proenzyme by stromelysin, a related metalloprotease. The proenzyme homodimer is unable to form a complex with TIMP. All TIMP-free forms of the proenzyme can be activated by stromelysin. The 92T4Cl-ClI complex can be activated to yield a complex active against both gelatin and fibrillar Type I collagen, suggesting a mechanism for cooperative action of two enzymes in reducing collagen fibrils to small peptides under physiologic conditions.