Activation of human interstitial procollagenase through direct cleavage of the Leu83-Thr84 bond by mast cell chymase.
Activation of human interstitial procollagenase through direct cleavage of the Leu83-Thr84 bond by mast cell chymase.
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DOI：
10.1016/s0021-9258(17)32427-4
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发表时间：
1994-07
期刊：
影响因子：
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通讯作者：
J. Saarinen;N. Kalkkinen;H. Welgus;P. Kovanen
中科院分区：
文献类型：
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作者：
J. Saarinen;N. Kalkkinen;H. Welgus;P. Kovanen
在炎症组织部位，以持续的基质降解为特征，基质金属蛋白酶作为潜伏前体分泌，只有在细胞外激活后才能进行蛋白水解。这些区域通常含有局部增多的肥大细胞，这些肥大细胞能够释放肝素蛋白聚糖和具有胰酶活性或既具有胰酶活性又具有凝乳酶活性的完全活性内多肽酶之间的复合物。我们研究了纯化的人皮肤溶酶在没有肝素（溶酶的生理关联物）和存在的情况下激活人间质前胶原酶（基质金属蛋白酶-1）的能力。我们的研究表明，乳糜酶以时间和浓度依赖的方式激活前胶原酶。肝素通过加速前胶原酶的裂解和阻止其进一步降解，显著提高了乳糜酶激活前胶原酶的速率。此外，我们发现乳糜酶通过切割Leu83-Thr84键直接激活前胶原酶，而不形成任何中间物种。这是一种新的前胶原酶激活机制，与目前研究的其他激活剂的激活机制形成鲜明对比。乳糜酶激活前胶原酶的能力表明，乳糜酶在肥大细胞与细胞外前胶原酶共存的组织部位的基质降解中起积极作用。
In inflamed tissue sites characterized by on-going matrix degradation, the matrix metalloproteinases are secreted as latent precursors which are capable of proteolysis only after extracellular activation. Such areas often contain locally increased numbers of mast cells capable of releasing complexes between heparin proteoglycans and fully active endopeptidases with either tryptic (tryptase) or both tryptic and chymotryptic (chymase) activity. We have examined the ability of purified human skin chymase to activate human interstitial procollagenase (matrix metalloproteinase-1) in the absence and presence of heparin, the physiologic associate of chymase. Our studies indicate that chymase activates procollagenase in a time- and concentration-dependent manner. Heparin was found to increase markedly the rate at which chymase activates procollagenase both by accelerating the cleavage of procollagenase and also by preventing its further degradation. Moreover, we found that chymase activates procollagenase directly by cleaving the Leu83-Thr84 bond, without formation of any intermediate species. This is a novel mechanism for procollagenase activation, which contrasts sharply with the activation mechanisms of other activators studied so far. The ability of chymase to activate procollagenase suggests that chymase plays an active role in matrix degradation at tissue sites where mast cells coexist with extracellular procollagenase.