Cleavages within the prodomain direct intracellular trafficking and degradation of mature bone morphogenetic protein-4
Cleavages within the prodomain direct intracellular trafficking and degradation of mature bone morphogenetic protein-4
复制标题
DOI：
10.1091/mbc.e04-08-0673
复制
发表时间：
2004-11-01
影响因子：
3.3
通讯作者：
Christian, JL
中科院分区：
文献类型：
--
作者：
Degnin, C;Jean, F;Christian, JL
骨形态发生蛋白 - 4前体（BMP - 4）最初在靠近成熟配体结构域的一个共有弗林蛋白酶基序（S1位点）处被切割，这使得随后能够在上游基序（S2位点）处进行切割。先前的研究表明，S2切割调节成熟BMP - 4的活性和信号传导范围，但这种调节发生的机制尚不清楚。在此，我们发现BMP - 4的前体结构域和成熟结构域在S1切割后仍非共价结合，形成一种易被快速降解的复合物。降解需要溶酶体和蛋白酶体的功能，并且与硫酸乙酰肝素蛋白聚糖的相互作用会增强降解。在S2位点的后续切割使成熟BMP - 4从前体结构域中释放出来，从而使蛋白质稳定。我们还表明，在酸性降低的条件下，S2位点（而非S1位点）的切割增强，这与两种切割发生在不同的亚细胞区室的可能性相符。基于这些结果，我们提出了一个模型，用于解释上游位点的切割如何在成熟BMP - 4从前体结构域释放后调节其活性和信号传导范围。
Pro bone morphogenetic protein-4 (BMP-4) is initially cleaved at a consensus furin motif adjacent to the mature ligand domain (the S1 site), and this allows for subsequent cleavage at an upstream motif (the S2 site). Previous studies have shown that S2 cleavage regulates the activity and signaling range of mature BMP-4, but the mechanism by which this occurs is unknown. Here, we show that the pro- and mature domains of BMP-4 remain noncovalently associated after S1 cleavage, generating a complex that is targeted for rapid degradation. Degradation requires lysosomal and proteosomal function and is enhanced by interaction with heparin sulfate proteoglycans. Subsequent cleavage at the S2 site liberates mature BMP-4 from the prodomain, thereby stabilizing the protein. We also show that cleavage at the S2, but not the S1 site, is enhanced at reduced pH, consistent with the possibility that the two cleavages occur in distinct subcellular compartments. Based on these results, we propose a model for how cleavage at the upstream site regulates the activity and signaling range of mature BMP-4 after it has been released from the prodomain.