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首页> 外文期刊>Journal of Molecular Biology >p38alpha MAP kinase dimers with swapped activation segments and a novel catalytic loop conformation.
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p38alpha MAP kinase dimers with swapped activation segments and a novel catalytic loop conformation.

机译：p38alpha MAP激酶二聚体具有交换的激活片段和新型催化环构象。

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Many protein kinase functions, including autophosphorylation in trans, require dimerization, possibly by activation segment exchange. Such dimers have been reported for a few autophosphorylating protein kinases, but not for mitogen-activated protein kinases (MAPKs). Activation of MAPKs proceeds not only via the well-characterized action of dual T/Y specificity MAPK kinases, phosphorylating both residues of the MAPK TxY activation loop motif, but also via a noncanonical activation pathway triggered by phosphorylation at Tyr323 and homodimerization. Here, we report the 2. 7-A-resolution structure of p38alpha MAPK from Salmo salar in a novel domain-swapped homodimeric form. The tyrosines of the conserved sequence YxAPE anchor the swapped activation segments in a configuration suitable for autophosphorylation in trans and provide a model for the noncanonical pathway. In the dimer, a structural unit containing Tyr323 is formed at a dimerization contact region that stabilizes the HRD catalytic loop in a unique inactive geometry. This feature is consistent with the requirement of Tyr323 phosphorylation for the initiation of the noncanonical pathway. Despite the interacting surface of more than 2600 A(2), the dimer is not obligate, as gel filtration shows the dimerization to occur only at relatively high concentrations. The transition from monomer to dimer involves a relatively simple hinged displacement of helix EF and adjacent residues. Thus, dimer formation is likely to be transient, compatible with functional requirements for autophosphorylation, allowing further modulation, for example, by scaffolding mechanisms.
机译：许多蛋白激酶功能（包括反式自身磷酸化）需要二聚化，可能是通过激活片段交换来实现的。已经报道了这种二聚体用于一些自磷酸化蛋白激酶，但没有用于丝裂原活化蛋白激酶（MAPK）。 MAPK的激活不仅通过双重T / Y特异性MAPK激酶的良好表征的作用进行，将MAPK TxY激活环基序的两个残基磷酸化，而且还通过Tyr323磷酸化和同二聚化触发的非规范激活途径进行。在这里，我们以新的域交换同型二聚体形式报告了来自Salmo salar的p38alpha MAPK的2. 7-A分辨率结构。保守序列YxAPE的酪氨酸以适合于反式自磷酸化的构型锚定交换的激活片段，并为非经典途径提供模型。在二聚体中，在二聚化接触区域形成包含Tyr323的结构单元，该结构单元将HRD催化环稳定在独特的惰性几何结构中。该特征与非典型途径的起始Tyr323磷酸化的要求是一致的。尽管有超过2600 A（2）的相互作用表面，但二聚体不是必需的，因为凝胶过滤显示二聚化仅在相对较高的浓度下发生。从单体到二聚体的转变涉及螺旋EF和相邻残基的相对简单的铰链置换。因此，二聚体的形成可能是瞬时的，与自磷酸化的功能要求兼容，从而允许进一步的调节，例如通过支架机制。

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