Structural basis for the function and regulation of the receptor protein tyrosine phosphatase CD45.
Structural basis for the function and regulation of the receptor protein tyrosine phosphatase CD45.
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DOI：
10.1084/jem.20041890
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发表时间：
2005-02-07
影响因子：
15.3
通讯作者：
Frederick, CA
中科院分区：
文献类型：
--
作者：
Nam, HJ;Poy, F;Saito, H;Frederick, CA
CD45是跨膜受体样蛋白酪氨酸磷酸酶（RPTPs）的原型成员，在免疫功能中具有重要作用。与许多其他RPTP一样，CD45的胞质区含有两个同源蛋白酪氨酸磷酸酶结构域，活性结构域1（D1）和催化受损结构域2（D2）。在这里，我们报告的晶体结构的细胞质D1D2段的人CD45在本地和磷酸酪氨酸肽结合的形式。D1和D2的三级结构非常相似，但双磷酸化的CD3+免疫受体酪氨酸基活化基序肽仅结合D1活性位点。D2“活性位点”显著偏离其它活性位点至排除任何催化活性的可能性的程度。D1和D2的相对方向与在白细胞常见抗原相关蛋白中观察到的非常相似，两个活性位点均处于开放构象，并且通过广泛的疏水性相互作用、氢键和盐桥网络受到限制。这种晶体结构与先前提出的CD45调节的楔形模型不相容。
CD45 is the prototypic member of transmembrane receptor-like protein tyrosine phosphatases (RPTPs) and has essential roles in immune functions. The cytoplasmic region of CD45, like many other RPTPs, contains two homologous protein tyrosine phosphatase domains, active domain 1 (D1) and catalytically impaired domain 2 (D2). Here, we report crystal structure of the cytoplasmic D1D2 segment of human CD45 in native and phosphotyrosyl peptide-bound forms. The tertiary structures of D1 and D2 are very similar, but doubly phosphorylated CD3ζ immunoreceptor tyrosine-based activation motif peptide binds only the D1 active site. The D2 “active site” deviates from the other active sites significantly to the extent that excludes any possibility of catalytic activity. The relative orientation of D1 and D2 is very similar to that observed in leukocyte common antigen–related protein with both active sites in an open conformation and is restrained through an extensive network of hydrophobic interactions, hydrogen bonds, and salt bridges. This crystal structure is incompatible with the wedge model previously suggested for CD45 regulation.
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