X-ray structure of human proMMP-1 - New insights into procollagenase activation and collagen binding
X-ray structure of human proMMP-1 - New insights into procollagenase activation and collagen binding
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DOI：
10.1074/jbc.m411084200
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发表时间：
2005-03-11
影响因子：
4.8
通讯作者：
Maskos, K
中科院分区：
文献类型：
--
作者：
Jozic, D;Bourenkov, G;Maskos, K
脊椎动物胶原酶是基质金属蛋白酶（MMP）家族的成员，可启动间质纤维胶原蛋白分解。它在许多生物过程中是必不可少的，并且不平衡的胶原溶解与诸如关节炎、癌症、动脉粥样硬化、动脉瘤和纤维化的疾病相关。这些金属蛋白酶作为无活性的前体前胶原酶（proMMP）从细胞分泌。为了深入了解它们的激活机制和胶原结合的结构基础，我们结晶了重组人proMMP-1并确定了其结构至2.2埃分辨率。催化金属蛋白酶结构域和C-末端血红素结合蛋白（Hpx）结构域显示了经典的MMP-折叠，但结构在表面环和结构域相互作用方面显示了新的特征。前结构域由三螺旋束形成，并提供了对proMMP-1的逐步激活机制的了解。前结构域与Hpx结构域相互作用，其影响Hpx结构域相对于催化结构域的位置。这种相互作用导致proMMP-1的“闭合”构型，这与先前对于活性MMP-1的结构观察到的“开放”构型相反。这是Hpx结构域相对于催化结构域的流动性的第一个证据，为理解胶原酶-胶原相互作用和随后的胶原溶解提供了重要线索。
Vertebrate collagenases, members of the matrix metalloproteinase (MMP) family, initiate interstitial fibrillar collagen breakdown. It is essential in many biological processes, and unbalanced collagenolysis is associated with diseases such as arthritis, cancer, atherosclerosis, aneurysm, and fibrosis. These metalloproteinases are secreted from the cell as inactive precursors, procollagenases (proMMPs). To gain insights into the structural basis of their activation mechanisms and collagen binding, we have crystallized recombinant human proMMP-1 and determined its structure to 2.2 Angstrom resolution. The catalytic metalloproteinase domain and the C-terminal hemopexin (Hpx) domain show the classical MMP-fold, but the structure has revealed new features in surface loops and domain interaction. The prodomain is formed by a three- helix bundle and gives insight into the stepwise activation mechanism of proMMP-1. The prodomain interacts with the Hpx domain, which affects the position of the Hpx domain relative to the catalytic domain. This interaction results in a "closed" configuration of proMMP-1 in contrast to the "open" configuration observed previously for the structure of active MMP-1. This is the first evidence of mobility of the Hpx domain in relation to the catalytic domain, providing an important clue toward the understanding of the collagenase-collagen interaction and subsequent collagenolysis.