Diffusion of MMPs on the Surface of Collagen Fibrils: The Mobile Cell Surface - Collagen Substratum Interface
Diffusion of MMPs on the Surface of Collagen Fibrils: The Mobile Cell Surface - Collagen Substratum Interface
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DOI：
10.1371/journal.pone.0024029
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发表时间：
2011-09-01
期刊：
影响因子：
3.7
通讯作者：
Goldberg, Gregory I.
中科院分区：
文献类型：
--
作者：
Collier, Ivan E.;Legant, Wesley;Goldberg, Gregory I.
MMPs催化的细胞外基质的重塑是发育和伤口愈合期间以及许多病理条件如纤维化和癌症中的形态发生现象的核心。我们以前已经证明，分泌的MMP-2被拴系到细胞表面和激活的MT 1-MMP/TIMP-2依赖性机制。所得的细胞表面胶原溶解复合物（MT 1-MMP）（2）/TIMP-2/MMP-2可以引发（MT 1-MMP）和完全（MMP-2）下层胶原原纤维的降解。仍然存在以下问题：基质识别的机制是什么，涉及两个结构的相对有限的流动性，细胞表面酶复合物和胶原纤维嵌入ECM？在这里，我们证明了复合物的所有组分都能够在胶原纤维的表面上进行性运动。MT 1-MMP的运动机制是一种偏向性扩散，偏向性成分依赖于其底物的蛋白水解，而不是三磷酸腺苷（ATP）水解。它类似于我们之前描述的MMP-1布朗棘轮。此外，MMP-2和MMP-9以及它们各自与TIMP-1和TIMP-2的复合物都能够在天然胶原原纤维表面上进行布朗扩散，而没有明显的解离，而MMP-9的二聚化使酶固定。最具启发性的发现是MT 1-MMP的酶活性的失活对小型化3D组织构建体中产生的细胞力具有可检测的负面影响。我们提出胶原溶解复合物（MT 1-MMP）（2）/TIMP-2/MMP-2代表了一个移动的细胞表面-胶原基质界面。MT 1-MMP作为与MMP-2复合的拴系到细胞表面的分子棘轮的生物学意义表明空间调节的细胞周围蛋白水解在细胞-基质相互作用中的作用的新机制。
Remodeling of the extracellular matrix catalyzed by MMPs is central to morphogenetic phenomena during development and wound healing as well as in numerous pathologic conditions such as fibrosis and cancer. We have previously demonstrated that secreted MMP-2 is tethered to the cell surface and activated by MT1-MMP/TIMP-2-dependent mechanism. The resulting cell-surface collagenolytic complex (MT1-MMP)(2)/TIMP-2/MMP-2 can initiate (MT1-MMP) and complete (MMP-2) degradation of an underlying collagen fibril. The following question remained: What is the mechanism of substrate recognition involving the two structures of relatively restricted mobility, the cell surface enzymatic complex and a collagen fibril embedded in the ECM? Here we demonstrate that all the components of the complex are capable of processive movement on a surface of the collagen fibril. The mechanism of MT1-MMP movement is a biased diffusion with the bias component dependent on the proteolysis of its substrate, not adenosine triphosphate (ATP) hydrolysis. It is similar to that of the MMP-1 Brownian ratchet we described earlier. In addition, both MMP-2 and MMP-9 as well as their respective complexes with TIMP-1 and -2 are capable of Brownian diffusion on the surface of native collagen fibrils without noticeable dissociation while the dimerization of MMP-9 renders the enzyme immobile. Most instructive is the finding that the inactivation of the enzymatic activity of MT1-MMP has a detectable negative effect on the cell force developed in miniaturized 3D tissue constructs. We propose that the collagenolytic complex (MT1-MMP)(2)/TIMP-2/MMP-2 represents a Mobile Cell Surface - Collagen Substratum Interface. The biological implications of MT1-MMP acting as a molecular ratchet tethered to the cell surface in complex with MMP-2 suggest a new mechanism for the role of spatially regulated peri-cellular proteolysis in cell-matrix interactions.