A secretory kinase complex regulates extracellular protein phosphorylation.
A secretory kinase complex regulates extracellular protein phosphorylation.
复制标题
DOI：
10.7554/elife.06120
复制
发表时间：
2015-03-19
期刊：
影响因子：
7.7
通讯作者：
Dixon JE
中科院分区：
文献类型：
--
作者：
Cui J;Xiao J;Tagliabracci VS;Wen J;Rahdar M;Dixon JE
虽然许多细胞外磷蛋白已被确定，分泌途径内的蛋白激酶只是最近才被发现，它们的调节几乎是未经探索的。Fam20C是生理性高尔基体酪蛋白激酶，其磷酸化许多分泌蛋白，并且对于适当的生物矿化至关重要。Fam20A是Fam20C的一种，是釉质形成所必需的，但Fam20A的生物化学功能尚不清楚。在这里，我们表明，Fam20A增强Fam20C激酶的活性，并促进釉基质蛋白在体外和细胞中的磷酸化。从机制上讲，Fam20A是一种假激酶，与Fam20C形成功能性复合物，该复合物增强分泌途径内的细胞外蛋白磷酸化。我们的研究结果阐明了Fam20C和Fam20A合作控制釉质形成的分子机制，并首次深入了解分泌途径磷酸化的调节。DOI：http://dx.doi.org/10.7554/eLife.06120.001有些蛋白质必须经过修饰才能有效地发挥作用。一种常见的修饰是在蛋白质上添加磷酸基团，这是由称为蛋白激酶的酶完成的。虽然大多数蛋白激酶作用于细胞内的蛋白质，但最近发现，一小群激酶在“分泌途径”中起作用，并修饰从细胞中释放（或分泌）的蛋白质。一种称为Fam20C的分泌途径激酶磷酸化广泛的分泌蛋白质，并有助于确保骨骼和牙齿的正常发育。具体来说，Fam20C和一种称为Fam20A的密切相关的蛋白质对于形成牙釉质非常重要，牙釉质是人体中最坚硬的物质，构成牙齿的外表面。然而，Fam20A的确切作用尚不清楚。Cui等人现在表明Fam20A与Fam20C结合，这增加了Fam20C磷酸化形成引导釉质矿物质沉积的“基质”的蛋白质的能力。此外，Fam20A中的突变导致Fam20C对釉质基质蛋白的磷酸化效率低下，并阻止适当的釉质形成。这些结果提出了一种可能性，即分泌激酶激活的类似机制在许多分泌蛋白需要快速磷酸化的其他生物过程中也可能很重要。DOI：http://dx.doi.org/10.7554/eLife.06120.002网站
Although numerous extracellular phosphoproteins have been identified, the protein kinases within the secretory pathway have only recently been discovered, and their regulation is virtually unexplored. Fam20C is the physiological Golgi casein kinase, which phosphorylates many secreted proteins and is critical for proper biomineralization. Fam20A, a Fam20C paralog, is essential for enamel formation, but the biochemical function of Fam20A is unknown. Here we show that Fam20A potentiates Fam20C kinase activity and promotes the phosphorylation of enamel matrix proteins in vitro and in cells. Mechanistically, Fam20A is a pseudokinase that forms a functional complex with Fam20C, and this complex enhances extracellular protein phosphorylation within the secretory pathway. Our findings shed light on the molecular mechanism by which Fam20C and Fam20A collaborate to control enamel formation, and provide the first insight into the regulation of secretory pathway phosphorylation. DOI: http://dx.doi.org/10.7554/eLife.06120.001 Some proteins must be modified in order to work effectively. One common modification is to add a phosphate group to the protein, which is performed by enzymes called protein kinases. Although most of the protein kinases work on proteins inside the cell, it was discovered recently that a small group of kinases work within the ‘secretory pathway’ and modify proteins that are released (or secreted) out of cells. One such secretory pathway kinase—called Fam20C—phosphorylates a wide range of secreted proteins and helps to ensure the proper development of bones and teeth. Specifically, Fam20C and a closely related protein called Fam20A are important for forming enamel, the hardest substance in human body, which makes up the outer surface of teeth. However, the exact role of Fam20A is unknown. Cui et al. now show that Fam20A binds to Fam20C, and this increases the ability of Fam20C to phosphorylate the proteins that form the ‘matrix’ that guides the deposition of the enamel minerals. Furthermore, mutations in Fam20A lead to the inefficient phosphorylation of enamel matrix proteins by Fam20C, and prevent proper enamel formation. The results raise the possibility that similar mechanisms of secretory kinase activation may also be important in other biological processes where many secreted proteins need to be phosphorylated rapidly. DOI: http://dx.doi.org/10.7554/eLife.06120.002