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首页> 外文期刊>Biochemistry >Drosophila TIMP Is a Potent Inhibitor of MMPs and TACE: Similarities in Structure and Function to TIMP-3.
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Drosophila TIMP Is a Potent Inhibitor of MMPs and TACE: Similarities in Structure and Function to TIMP-3.

机译：果蝇TIMP是MMP和TACE的有效抑制剂：在结构和功能上与TIMP-3相似。

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摘要

The four tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors that regulate the activity of matrix metalloproteinases (MMPs) and certain disintegrin and metalloproteinase (ADAM) family proteases in mammals. The protease inhibitory activity is present in the N-terminal domains of TIMPs (N-TIMPs). In this work, the N-terminal inhibitory domain of the only TIMP produced by Drosophila (dN-TIMP) was expressed in Escherichia coli and folded in vitro. The purified recombinant protein is a potent inhibitor of human MMPs, including membrane-type 1-MMP, although it lacks a disulfide bond that is conserved in all other known N-TIMPs. Titration with the catalytic domain of human MMP-3 [MMP-3(DeltaC)] showed that dN-TIMP prepared by this method is correctly folded and fully active. dN-TIMP also inhibits, in vitro, the activity of the only two MMPs of Drosophila, dm1- and dm2-MMPs, indicating that the Drosophila TIMP is an endogenous inhibitor of the Drosophila MMPs. dN-TIMP resembles mammalian N-TIMP-3 in strongly inhibiting human tumor necrosis factor-alpha-converting enzyme (TACE/ADAM17) but is a weak inhibitor of human ADAM10. Models of the structures of dN-TIMP and N-TIMP-3 are strikingly similar in surface charge distribution, which may explain their functional similarity. Although the gene duplication events that led to the evolutionary development of the four mammalian TIMPs might be expected to be associated with functional specialization, Timp-3 appears to have conserved most of the functions of the ancestral TIMP gene.
机译：四种金属蛋白酶组织抑制剂（TIMPs）是内源性抑制剂，可调节哺乳动物中基质金属蛋白酶（MMP）以及某些整联蛋白和金属蛋白酶（ADAM）家族蛋白酶的活性。蛋白酶抑制活性存在于TIMP（N-TIMP）的N-末端结构域中。在这项工作中，由果蝇产生的唯一TIMP（dN-TIMP）的N端抑制域在大肠杆菌中表达并在体外折叠。纯化的重组蛋白是人MMP（包括膜型1-MMP）的有效抑制剂，尽管它缺少在所有其他已知N-TIMP中都保守的二硫键。用人MMP-3 [MMP-3（DeltaC）]的催化结构域滴定表明，用此方法制备的dN-TIMP正确折叠并具有完全活性。 dN-TIMP还可以在体外抑制果蝇仅有的两个MMP，dm1-和dm2-MMP的活性，这表明果蝇TIMP是果蝇MMP的内源性抑制剂。 dN-TIMP在强烈抑制人类肿瘤坏死因子-α转化酶（TACE / ADAM17）方面类似于哺乳动物N-TIMP-3，但它是人类ADAM10的弱抑制剂。 dN-TIMP和N-TIMP-3的结构模型在表面电荷分布方面极为相似，这可以解释它们的功能相似性。尽管可以预期导致四种哺乳动物TIMPs进化发展的基因复制事件与功能特化有关，但Timp-3似乎保留了祖先TIMP基因的大部分功能。

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