Department of Physical Biochemistry, Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Strasse 11, Dortmund 44227, Germany.
Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):17945-50. doi: 10.1073/pnas.1113133108. Epub 2011 Oct 19.
The causative agent of Legionnaires disease, Legionella pneumophila, injects several hundred proteins into the cell it infects, many of which interfere with or exploit vesicular transport processes. One of these proteins, LidA, has been described as a Rab effector (i.e., a molecule that interacts preferentially with the GTP-bound form of Rab). We describe here the structure and biochemistry of a complex between the Rab-binding domain of LidA and active Rab8a. LidA displays structural peculiarities in binding to Rab8a, forming a considerably extended interface in comparison to known mammalian Rab effectors, and involving regions of the GTPase that are not seen in other Rab:effector complexes. In keeping with this extended binding interface, which involves four α-helices and two pillar-like structures of LidA, the stability of LidA-Rab interactions is dramatically greater than for other such complexes. For Rab1b and Rab8a, these affinities are extraordinarily high, but for the more weakly bound Rab6a, K(d) values of 4 nM for the inactive and 30 pM for the active form were found. Rab1b and Rab8a appear to bind LidA with K(d) values in the low picomolar range, making LidA a Rab supereffector.
军团病的病原体嗜肺军团菌向其感染的细胞中注入了几百种蛋白质，其中许多蛋白质会干扰或利用小泡运输过程。这些蛋白质中的一种 LidA 被描述为 Rab 效应物（即优先与 Rab 的 GTP 结合形式相互作用的分子）。我们在这里描述了 LidA 的 Rab 结合域与活性 Rab8a 之间的复合物的结构和生物化学性质。与已知的哺乳动物 Rab 效应物相比，LidA 在与 Rab8a 结合时显示出结构上的特殊性，形成了一个相当延伸的界面，并且涉及到其他 Rab:效应物复合物中未见到的 GTPase 区域。与涉及四个α-螺旋和 LidA 的两个柱形结构的这种扩展结合界面一致，LidA-Rab 相互作用的稳定性远远大于其他此类复合物。对于 Rab1b 和 Rab8a，这些亲和力非常高，但对于结合较弱的 Rab6a，发现非活性形式的 K(d)值为 4 nM，而活性形式的 K(d)值为 30 pM。Rab1b 和 Rab8a 似乎以低皮摩尔范围内的 K(d)值结合 LidA，使 LidA 成为 Rab 超级效应物。
