Anantharaman Vivek, Balaji S, Aravind L
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
Biol Direct. 2006 Sep 5;1:25. doi: 10.1186/1745-6150-1-25.
The mechanism by which the signals are transmitted between receptor and effector domains in multi-domain signaling proteins is poorly understood.
Using sensitive sequence analysis methods we identify a conserved helical segment of around 40 residues in a wide range of signaling proteins, including numerous sensor histidine kinases such as Sln1p, and receptor guanylyl cyclases such as the atrial natriuretic peptide receptor and nitric oxide receptors. We term this helical segment the signaling (S)-helix and present evidence that it forms a novel parallel coiled-coil element, distinct from previously known helical segments in signaling proteins, such as the Dimerization-Histidine phosphotransfer module of histidine kinases, the intra-cellular domains of the chemotaxis receptors, inter-GAF domain helical linkers and the alpha-helical HAMP module. Analysis of domain architectures allowed us to reconstruct the domain-neighborhood graph for the S-helix, which showed that the S-helix almost always occurs between two signaling domains. Several striking patterns in the domain neighborhood of the S-helix also became evident from the graph. It most often separates diverse N-terminal sensory domains from various C-terminal catalytic signaling domains such as histidine kinases, cNMP cyclase, PP2C phosphatases, NtrC-like AAA+ ATPases and diguanylate cyclases. It might also occur between two sensory domains such as PAS domains and occasionally between a DNA-binding HTH domain and a sensory domain. The sequence conservation pattern of the S-helix revealed the presence of a unique constellation of polar residues in the dimer-interface positions within the central heptad of the coiled-coil formed by the S-helix.
Combining these observations with previously reported mutagenesis studies on different S-helix-containing proteins we suggest that it functions as a switch that prevents constitutive activation of linked downstream signaling domains. However, upon occurrence of specific conformational changes due to binding of ligand or other sensory inputs in a linked upstream domain it transmits the signal to the downstream domain. Thus, the S-helix represents one of the most prevalent functional themes involved in the flow of signals between modules in diverse prokaryote-type multi-domain signaling proteins.
This article was reviewed by Frank Eisenhaber, Arcady Mushegian and Sandor Pongor.
多结构域信号蛋白中受体与效应器结构域之间信号传递的机制尚不清楚。
我们使用灵敏的序列分析方法，在多种信号蛋白中鉴定出一段约40个残基的保守螺旋片段，包括许多传感组氨酸激酶，如Sln1p，以及受体鸟苷酸环化酶，如心钠素受体和一氧化氮受体。我们将此螺旋片段称为信号（S）螺旋，并提供证据表明它形成了一种新型的平行卷曲螺旋元件，不同于信号蛋白中先前已知的螺旋片段，如组氨酸激酶的二聚化 - 组氨酸磷酸转移模块、趋化受体的细胞内结构域、GAF结构域间螺旋连接体以及α - 螺旋HAMP模块。对结构域架构的分析使我们能够重建S螺旋的结构域邻接图，结果表明S螺旋几乎总是出现在两个信号结构域之间。从该图中还可以明显看出S螺旋结构域邻接中的几个显著模式。它最常将不同的N端传感结构域与各种C端催化信号结构域分开，如组氨酸激酶、cNMP环化酶、PP2C磷酸酶、NtrC样AAA + ATP酶和双鸟苷酸环化酶。它也可能出现在两个传感结构域之间，如PAS结构域，偶尔也出现在DNA结合HTH结构域和传感结构域之间。S螺旋的序列保守模式揭示了在由S螺旋形成的卷曲螺旋中央七肽的二聚体界面位置存在一组独特的极性残基。
将这些观察结果与先前报道的对不同含S螺旋蛋白的诱变研究相结合，我们认为它起到开关的作用，防止连接的下游信号结构域的组成性激活。然而，当由于配体结合或连接的上游结构域中的其他传感输入而发生特定构象变化时，它会将信号传递到下游结构域。因此，S螺旋代表了不同原核生物型多结构域信号蛋白中模块间信号流动所涉及的最普遍的功能主题之一。
本文由Frank Eisenhaber、Arcady Mushegian和Sandor Pongor评审。
