Department of Protein Evolution, Max-Planck-Institute for Developmental Biology, Spemannstr. 35, D-72076 Tuebingen, Germany.
J Mol Biol. 2010 Apr 16;397(5):1156-74. doi: 10.1016/j.jmb.2010.02.031. Epub 2010 Feb 23.
Homodimeric receptors with one or two transmembrane (TM) segments per monomer are universal to life and represent the largest and most diverse group of cellular TM receptors. They frequently share domain types across phyla and, in some cases, have been recombined experimentally into functional chimeras (e.g., the bacterial aspartate chemoreceptor with the human insulin receptor), suggesting that they have a common mechanism. The nature of this mechanism, however, is still being debated. We have proposed a new model for transduction mechanism by axial helix rotation, based on the structure of a widespread domain, HAMP, that frequently occurs in direct continuation of the last TM segment, primarily in histidine kinases and chemoreceptors. Here we show by statistical analysis that HAMP domain sequences have biophysical properties compatible with the two conformations proposed by the model. The analysis also identifies three networks of coevolving residues, which allow the mechanism to subdivide into individual steps. The most extended of these networks is specific for membrane-bound HAMP domains and most likely accepts the signal from the TM helices. In a classification based on sequence clustering, these HAMPs form a central supercluster, surrounded by smaller clusters of divergent HAMPs, which typically combine into arrays of up to 31 consecutive copies and accept conformational input from other HAMP domains. Unexpectedly, the classification shows a division between domains of histidine kinases and those of chemoreceptors; thus, except for a few versatile lineages, HAMP domains are largely specific for one particular output domain. Within proteins using a given output domain, HAMP domains also show extensive coevolution with histidine kinases, but not with chemoreceptors. We attribute the greater capability for recombination among chemoreceptors to their acquisition of a reversible modification system, which acts as a capacitor for the initially deleterious effects of combining domains optimized in different contexts.
同二聚体受体每个单体具有一个或两个跨膜 (TM) 片段，是生命的普遍存在形式，代表着最大和最多样化的细胞 TM 受体群体。它们经常在门之间共享结构域类型，在某些情况下，已经通过实验重组为功能性嵌合体（例如，细菌天冬氨酸化学感受器与人类胰岛素受体），这表明它们具有共同的机制。然而，这种机制的性质仍在争论中。我们提出了一种基于广泛存在的结构域 HAMP 的轴向螺旋旋转转导机制的新模型，该结构域通常直接延续最后一个 TM 片段，主要存在于组氨酸激酶和化学感受器中。在这里，我们通过统计分析表明，HAMP 结构域序列具有与模型提出的两种构象兼容的生物物理特性。该分析还确定了三个共进化残基网络，这些网络允许机制细分为单个步骤。其中最扩展的网络特定于膜结合的 HAMP 结构域，并且很可能接受来自 TM 螺旋的信号。在基于序列聚类的分类中，这些 HAMP 形成一个中央超级簇，周围是较小的发散 HAMP 簇，这些簇通常组合成多达 31 个连续拷贝的数组，并接受来自其他 HAMP 结构域的构象输入。出乎意料的是，该分类显示了组氨酸激酶和化学感受器结构域之间的划分；因此，除了少数多功能谱系外，HAMP 结构域在很大程度上是特定于一个特定的输出结构域的。在使用给定输出结构域的蛋白质中，HAMP 结构域也与组氨酸激酶表现出广泛的共进化，但与化学感受器没有共进化。我们将化学感受器之间具有更大重组能力归因于它们获得了可逆修饰系统，该系统作为在不同上下文中优化的结构域组合的最初有害影响的电容器。
