Receptor-like protein tyrosine phosphatase α homodimerizes on the cell surface
Receptor-like protein tyrosine phosphatase α homodimerizes on the cell surface
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DOI：
10.1128/mcb.20.16.5917-5929.2000
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发表时间：
2000-08-01
影响因子：
5.3
通讯作者：
Hunter, T
中科院分区：
文献类型：
--
作者：
Jiang, GQ;Den Hertog, J;Hunter, T
我们以前报道，受体蛋白酪氨酸磷酸酶α的N-末端D1催化结构域，（RPTP α）在晶体结构中形成对称的抑制二聚体，其中来自一个单体的螺旋-转角-螺旋楔形元件插入另一个单体的催化裂缝中，以前的功能研究也表明，二聚化抑制CD 45嵌合RPTP的生物活性和CD 45嵌合RPTP的催化活性。最近，我们还表明，强制二聚化以楔依赖性方式抑制全长RPTPa的生物活性。这种抑制的生理意义是未知的，由于缺乏对RPTPa二聚化如何在体内调节的理解。在这项研究中，我们表明，瞬时表达的细胞表面RPTP α主要以同源二聚体的形式存在，这表明二聚化介导的RPTP α生物活性抑制可能与生理相关。与我们已发表和未发表的晶体学数据一致，我们表明D1催化结构域楔形区的突变和整个D2催化结构域的缺失独立地减少但没有消除RPTP α同源二聚化，这表明这两个结构域都是关键性的，但都不是同源二聚化所必需的。最后，我们还提供了RPTPa胞外结构域和跨膜结构域都能够独立地同源二聚化的证据。这些结果使我们提出了一个拉链模型，其中无活性的RPTP α二聚体通过多个相对弱的二聚化界面来稳定，以这种方式的二聚化将为RPTP α的负调控提供潜在的机制。这种RPTP α二聚体可以被诱导单体化的细胞外配体或细胞内结合蛋白激活，或者被诱导二聚体开放构象的细胞内信号传导事件激活。
We reported previously that the N-terminal D1 catalytic domain of receptor protein-tyrosine phosphatase alpha (RPTP alpha) forms a symmetrical, inhibited dimer in a crystal structure, in which a helix-turn-helix wedge element from one monomer is inserted into the catalytic cleft of the other monomer, Previous functional studies also suggested that dimerization inhibits the biological activity of a CD45 chimeric RPTP and the catalytic activity of an isolated RPTP sigma D1 catalytic domain, Most recently, we have also shown that enforced dimerization inhibits the biological activity of full-length RPTPa in a wedge-dependent manner. The physiological significance of such inhibition is unknown, due to a lack of understanding of how RPTPa dimerization is regulated in vivo. In this study, we show that transiently expressed cell surface RPTP alpha exists predominantly as homodimers, suggesting that dimerization-mediated inhibition of RPTP alpha biological activity is likely to be physiologically relevant. Consistent with our published and unpublished crystallographic data, we show that mutations in the wedge region of D1 catalytic domain and deletion of the entire D2 catalytic domain independently reduced but did not abolish RPTP alpha homodimerization, suggesting that both domains are critically involved but that neither is essential for homodimerization. Finally, we also provide evidence that both the RPTPa extracellular domain and the transmembrane domain were independently able to homodimerize, These results lead us to propose a zipper model in which inactive RPTP alpha dimers are stabilized by multiple, relatively weak dimerization interfaces, Dimerization in this manner would provide a potential mechanism for negative regulation of RPTP alpha. Such RPTP alpha dimers could be activated by extracellular ligands or intracellular binding proteins that induce monomerization or by intracellular signaling events that induce an open conformation of the dimer.