Glycosaminoglycans influence enzyme activity of MMP2 and MMP2/TIMP3 complex formation - Insights at cellular and molecular level
Glycosaminoglycans influence enzyme activity of MMP2 and MMP2/TIMP3 complex formation - Insights at cellular and molecular level
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DOI：
10.1038/s41598-019-41355-2
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发表时间：
2019-03-20
影响因子：
4.6
通讯作者：
Hempel, Ute
中科院分区：
文献类型：
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作者：
Ruiz-Gomez, Gloria;Vogel, Sarah;Hempel, Ute
细胞外基质（ECM）是一个高度动态的网络，通过微调蛋白质形成和降解平衡不断重塑。基质金属蛋白酶 (MMP) 是 ECM 降解的关键协调者。它们的活性由金属蛋白酶（TIMP）和糖胺聚糖（GAG）的组织抑制剂控制。在这里，我们利用人骨髓基质细胞的体外实验、计算机对接和分子动力学模拟，研究了 MMP2 与不同 GAG（硫酸软骨素、透明质酸 (HA)、硫酸化透明质酸 (SH) 和肝素 (HE)）的分子相互作用，以及 GAG 对 MMP2/TIMP3 复合物形成的影响。 SH 和 HE 影响 MMP2 和 TIMP3 蛋白水平以及 MMP2 活性。只有 SH 支持两种蛋白质在纤维状结构中的排列，根据我们的分子模型，这可能是由于 MMP2-血红素结构域和 TIMP3-C 末端尾之间的相互作用的稳定所致。根据最终三元复合物形成的时间顺序，我们的模型表明 SH 和 HA 可以分别通过阻止或支持它们的相互作用来影响 TIMP3 诱导的 MMP2 抑制。我们的实验和理论相结合的方法为 GAG 如何干扰 MMP2 活性和 MMP2/TIMP3 复合物形成提供了有价值的新见解。结果证明 GAG 是 ECM 重塑的精细平衡干预的有前途的分子。
The extracellular matrix (ECM) is a highly dynamic network constantly remodeled by a fine-tuned protein formation and degradation balance. Matrix metalloproteinases (MMPs) constitute key orchestrators of ECM degradation. Their activity is controlled by tissue inhibitors of metalloproteinases (TIMPs) and glycosaminoglycans (GAG). Here, we investigated the molecular interplay of MMP2 with different GAG (chondroitin sulfate, hyaluronan (HA), sulfated hyaluronan (SH) and heparin (HE)) and the impact of GAG on MMP2/TIMP3 complex formation using in vitro-experiments with human bone marrow stromal cells, in silico docking and molecular dynamics simulations. SH and HE influenced MMP2 and TIMP3 protein levels and MMP2 activity. Only SH supported the alignment of both proteins in fibrillar-like structures, which, based on our molecular models, would be due to a stabilization of the interactions between MMP2-hemopexin domain and TIMP3-C-terminal tail. Dependent on the temporal sequential order in which the final ternary complex was formed, our models indicated that SH and HA can affect TIMP3-induced MMP2 inhibition through precluding or supporting their interactions, respectively. Our combined experimental and theoretical approach provides valuable new insights on how GAG interfere with MMP2 activity and MMP2/TIMP3 complex formation. The results obtained evidence GAG as promising molecules for fine-balanced intervention of ECM remodeling.