Comprehensive Analysis of HAMP Domains: Implications for Transmembrane Signal Transduction
Comprehensive Analysis of HAMP Domains: Implications for Transmembrane Signal Transduction
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DOI：
10.1016/j.jmb.2010.02.031
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发表时间：
2010-04-16
影响因子：
5.6
通讯作者：
Lupas, Andrei N.
中科院分区：
文献类型：
--
作者：
Dunin-Horkawicz, Stanislaw;Lupas, Andrei N.
每个单体具有一个或两个跨膜 (TM) 片段的同二聚受体在生命中是普遍存在的，代表了最大且最多样化的细胞 TM 受体群体。它们经常在各个门之间共享结构域类型，并且在某些情况下，已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。我们基于广泛的结构域 HAMP 的结构，提出了一种通过轴向螺旋旋转转导机制的新模型，HAMP 经常出现在最后一个 TM 片段的直接延续中，主要出现在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同进化残基网络，这使得该机制可以细分为单独的步骤。这些网络中最延伸的网络是膜结合 HAMP 结构域特有的，并且最有可能接受来自 TM 螺旋的信号。在基于序列聚类的分类中，这些 HAMP 形成一个中心超簇，周围环绕着较小的不同 HAMP 簇，这些簇通常组合成最多 31 个连续拷贝的阵列，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域和化学感受器域之间的划分；因此，除了少数通用谱系外，HAMP 结构域在很大程度上是针对某一特定输出结构域的。在使用给定输出结构域的蛋白质中，HAMP 结构域还显示出与组氨酸激酶的广泛共同进化，但不与化学感受器共同进化。我们将化学感受器之间更大的重组能力归因于它们获得了可逆修饰系统，该系统充当电容器，以消除在不同环境下优化的组合域的最初有害影响。 (C) 2010 Elsevier Ltd. 保留所有权利。
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. (C) 2010 Elsevier Ltd. All rights reserved.