Structural basis for inhibition of receptor protein-tyrosine phosphatase-alpha by dimerization
Structural basis for inhibition of receptor protein-tyrosine phosphatase-alpha by dimerization
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DOI：
10.1038/382555a0
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发表时间：
1996-08-08
期刊：
影响因子：
64.8
通讯作者：
Noel, JP
中科院分区：
文献类型：
--
作者：
Bilwes, AM;denHertog, J;Noel, JP
受体样蛋白酪氨酸磷酸酶 (RPTP) 与其非受体对应物一样，可调节源自蛋白酪氨酸激酶作用的含磷酸酪氨酸蛋白的水平 (1)。 RPTP 是 I 型整合膜蛋白，其胞质区域包含一个或两个催化结构域 (2)。目前尚不清楚细胞外配体是否调节 RPTP 的活性。在这里，我们描述了典型 RPTP（鼠 RPTP α）的近膜催化结构域 (D1) 的晶体结构。与 PTP1B 折叠的显着结构偏差存在于 RPTP α D1 的氨基末端地狱转角螺旋片段（残基 214 至 242）内，并且在残基 211-213 和 458-461 之间形成独特的双链 β 折叠。 N 端片段的转角插入二元相关 D1 单体的活性位点。基于两个独立的晶体结构、序列比对和已报道的 EGF 受体/CD45 嵌合体 (3) 的生物活性，我们提出二聚化和活性位点阻断是下调 RPTP α 和其他 RBTP 催化活性的重要生理机制。
RECEPTOR-LIKE protein-tyrosine phosphatases (RPTPs), like their non-receptor counterparts, regulate the level of phosphotyrosine-containing proteins derived from the action of protein-tyrosine kinases(1). RPTPs are type-I integral membrane proteins which contain one or two catalytic domains in their cytoplasmic region(2). It is not known whether extracellular ligands regulate the activity of RPTPs. Here we describe the crystal structure of the membrane-proximal catalytic domain (D1) of a typical RPTP, murine RPTP alpha. Significant structural deviations from the PTP1B fold reside within the amino-terminal hells-turn-helix segment of RPTP alpha D1 (residues 214 to 242) and a distinctive two stranded beta-sheet formed between residues 211-213 and 458-461. The turn of the N-terminal segment inserts into the active site of a dyad-related D1 monomer. On the basis of two independent crystal structures, sequence alignments, and the reported biological activity of EGF receptor/CD45 chimaeras(3), we propose that dimerization and active-site blockage is a physiologically important mechanism for downregulating the catalytic activity of RPTP alpha and other RBTPs.