The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity.
The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity.
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DOI：
10.1016/j.bbamcr.2010.01.003
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发表时间：
2010-01
期刊：
影响因子：
--
通讯作者：
Nagase H
中科院分区：
文献类型：
--
作者：
Brew K;Nagase H
金属蛋白酶组织抑制因子(TIMPs)广泛存在于动物界，人类基因组中含有4个相似的TIMPs 1~4编码基因。TIMPs最初被认为是基质金属蛋白酶(MMPs)的抑制剂，但现在发现它们的活性范围更广，因为它包括抑制几种去整合素-金属蛋白酶，ADAMS和ADAMTS。因此，TIMP是降解细胞外基质和脱落细胞表面分子的金属蛋白酶的关键调节因子。对TIMP-MMP络合物的结构研究已经阐明了TIMP的抑制机制以及它们与靶酶相互作用的多个位点，从而允许TIMP变体的产生，选择性地抑制不同组的金属蛋白酶。由于TIMP可以通过它们与蛋白酶的相互作用而引起分子动力学的变化，因此设计这些变体变得复杂。TIMP还具有不依赖于金属蛋白酶的生物活性，包括对细胞生长和分化、细胞迁移、抗血管生成、抗和促凋亡以及突触可塑性的影响。负责其中一些活动的受体已经被确定，并对它们的信号通路进行了研究。利用特定TIMP基因缺失的小鼠进行的一系列研究阐明了这些分子在生物学和病理学中的重要性。
Tissue inhibitors of metalloproteinases (TIMPs) are widely distributed in the animal kingdom and the human genome contains four paralogous genes encoding TIMPs 1 to 4. TIMPs were originally characterized as inhibitors of matrix metalloproteinases (MMPs), but their range of activities has now been found to be broader as it includes the inhibition of several of the disintegrin-metalloproteinases, ADAMs and ADAMTSs. TIMPs are therefore key regulators of the metalloproteinases that degrade the extracellular matrix and shed cell surface molecules. Structural studies of TIMP–MMP complexes have elucidated the inhibition mechanism of TIMPs and the multiple sites through which they interact with target enzymes, allowing the generation of TIMP variants that selectively inhibit different groups of metalloproteinases. Engineering such variants is complicated by the fact that TIMPs can undergo changes in molecular dynamics induced by their interactions with proteases. TIMPs also have biological activities that are independent of metalloproteinases; these include effects on cell growth and differentiation, cell migration, anti-angiogenesis, anti- and pro-apoptosis, and synaptic plasticity. Receptors responsible for some of these activities have been identified and their signaling pathways have been investigated. A series of studies using mice with specific TIMP gene deletions has illuminated the importance of these molecules in biology and pathology.
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