Bone morphogenetic protein-1/tolloid-like proteinases process dentin matrix protein-1
Bone morphogenetic protein-1/tolloid-like proteinases process dentin matrix protein-1
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DOI：
10.1074/jbc.m310179200
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发表时间：
2004-01-09
影响因子：
4.8
通讯作者：
Greenspan, DS
中科院分区：
文献类型：
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作者：
Steiglitz, BM;Ayala, M;Greenspan, DS
骨形态发生蛋白-1（BMP-1）/Tolloid样金属蛋白酶通过生物合成将前体蛋白转化为成熟的功能形式，在哺乳动物细胞外基质（ECM）的形成中起着关键作用。这些蛋白酶可能通过激活转化生长因子β样BMP在骨形成中发挥进一步的作用。牙本质基质蛋白-1（Dentin matrix protein-1，DMP 1）在组装过程中沉积到ECM中并参与骨和牙齿的初始矿化，被认为在体内经历蛋白水解以产生在矿化组织提取物中发现的功能性切割片段。在这里，我们已经产生了重组DMP 1，并证明它是裂解，在不同程度上，由所有四种哺乳动物BMP-1/Tolloid样蛋白酶，以产生类似的片段大小的那些先前从骨分离。与BMP-1/Tolloid样蛋白酶在DMP 1的生理加工中的可能作用一致，由BMP-1切割DMP 1产生的产物的NH 2末端序列与从在预测的DMP 1位点处的加工中预测的那些相匹配，所述预测的DMP 1位点显示序列的最大跨物种保守性。此外，来自小鼠胚胎的成纤维细胞编码四种哺乳动物BMP 1/Tolloid样蛋白酶中的三种的基因纯合无效，似乎在加工DMP 1方面有缺陷。因此，BMP-1-Tolloid样蛋白酶在矿化组织的形成中的进一步作用是通过DMP 1的蛋白水解加工来指示的。
Bone morphogenetic protein-1 (BMP-1)/Tolloid-like metalloproteinases play key roles in formation of mammalian extracellular matrix (ECM), through the biosynthetic conversion of precursor proteins into their mature functional forms. These proteinases probably play a further role in formation of bone through activation of transforming growth factor beta-like BMPs. Dentin matrix protein-1 (DMP1), deposited into the ECM during assembly and involved in initiating mineralization of bones and teeth, is thought to undergo proteolysis in vivo to generate functional cleavage fragments found in extracts of mineralized tissues. Here, we have generated recombinant DMP1 and demonstrate that it is cleaved, to varying extents, by all four mammalian BMP-1/Tolloid-like proteinases, to generate fragments similar in size to those previously isolated from bone. Consistent with possible roles for the BMP-1/Tolloid-like proteinases in the physiological processing of DMP1, NH2-terminal sequences of products generated by BMP-1 cleavage of DMP1 match those predicted from processing at the predicted DMP1 site that shows greatest cross-species conservation of sequences. Moreover, fibroblasts derived from mouse embryos homozygous null for genes encoding three of the four mammalian BMP1/Tolloid-like proteinases appear to be deficient in processing of DMP1. Thus, a further role for BMP-1-Tolloid-like proteinases in formation of mineralized tissues is indicated, via proteolytic processing of DMP1.