Molecular Mechanism of Type I Collagen Homotrimer Resistance to Mammalian Collagenases
Molecular Mechanism of Type I Collagen Homotrimer Resistance to Mammalian Collagenases
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DOI：
10.1074/jbc.m110.102079
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发表时间：
2010-07-16
影响因子：
4.8
通讯作者：
Leikin, Sergey
中科院分区：
文献类型：
--
作者：
Han, Sejin;Makareeva, Elena;Leikin, Sergey
I型胶原蛋白的裂解对组织重塑至关重要，但其同型三聚体异构体对所有胶原酶都具有抗性。同源三聚体出现在胎儿组织、纤维化和癌症中，它们的胶原酶抵抗可能在其中起重要的生理作用。为了了解这种耐药性的机制，我们研究了α 1(I)(3)同源三聚体和正常α 1(I)(2) α 2(I)异源三聚体与成纤维细胞胶原酶（MMP-1）的相互作用。相似的MMP-1与两种同工异构体的结合以及相似的解旋α 1(I)和α 2(I)链的裂解效率表明，在胶原酶裂解位点，同源三聚体三螺旋的解旋效率较低，但稳定性更高。解绕是将单个链放入酶的催化裂孔中所必需的，是两种胶原同工型的限速裂解步骤。对比分析同种和异源三聚体的裂解动力学发现，MMP-1结合促进随机螺旋解绕，解决了胶原酶作用不同模型之间的争议。
Type I collagen cleavage is crucial for tissue remodeling, but its homotrimeric isoform is resistant to all collagenases. The homotrimers occur in fetal tissues, fibrosis, and cancer, where their collagenase resistance may play an important physiological role. To understand the mechanism of this resistance, we studied interactions of alpha 1(I)(3) homotrimers and normal alpha 1(I)(2)alpha 2(I) heterotrimers with fibroblast collagenase (MMP-1). Similar MMP-1 binding to the two isoforms and similar cleavage efficiency of unwound alpha 1(I) and alpha 2(I) chains suggested increased stability and less efficient unwinding of the homotrimer triple helix at the collagenase cleavage site. The unwinding, necessary for placing individual chains inside the catalytic cleft of the enzyme, was the rate-limiting cleavage step for both collagen isoforms. Comparative analysis of the homo-and heterotrimer cleavage kinetics revealed that MMP-1 binding promotes stochastic helix unwinding, resolving the controversy between different models of collagenase action.