A generalized allosteric mechanism for cis-regulated cyclic nucleotide binding domains
A generalized allosteric mechanism for cis-regulated cyclic nucleotide binding domains
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DOI：
10.1371/journal.pcbi.1000056
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发表时间：
2008-04-01
影响因子：
4.3
通讯作者：
Ten Eyck, Lynn F.
中科院分区：
文献类型：
--
作者：
Kornev, Alexandr P.;Taylor, Susan S.;Ten Eyck, Lynn F.
环核苷酸（cAMP和cGMP）调节多种细胞内过程，因此引起了分子和结构生物学家的广泛兴趣。为了研究不同环核苷酸结合（CNB）结构域的变构机制，我们使用一种新的生物信息学方法：局部空间模式比对（local spatial pattern alignment）来比较cAMP结合和cAMP不结合的结构（PKA、Epac和两个离子通道）。我们的分析突出了四个主要的保守结构基序：1）磷酸结合盒（PBC），其结合cAMP核糖-磷酸，2）“铰链”，一种柔性螺旋，其接触PBC，3）β（2，3）环，其提供来自PBC的不变精氨酸的精确定位，和4）由N-末端螺旋组成的保守结构元件，八个残基环和A-螺旋（N3 A-基序）。PBC和铰链被包括在先前报道的变构模型中，而β（2，3）环和N3 A基序作为保守元件的定义是新颖的。N3 A基序被发现在所有顺式调节CNB域，我们提出了一个模型，在这些领域的变构机制。分解代谢物基因激活蛋白（CAP）代表了一个反式调节的CNB结构域家族：它不含N3 A基序，其长程变构相互作用与顺式调节的CNB结构域有很大不同。
Cyclic nucleotides (cAMP and cGMP) regulate multiple intracellular processes and are thus of a great general interest for molecular and structural biologists. To study the allosteric mechanism of different cyclic nucleotide binding (CNB) domains, we compared cAMP-bound and cAMP-free structures (PKA, Epac, and two ionic channels) using a new bioinformatics method: local spatial pattern alignment. Our analysis highlights four major conserved structural motifs: 1) the phosphate binding cassette (PBC), which binds the cAMP ribose-phosphate, 2) the "hinge,'' a flexible helix, which contacts the PBC, 3) the beta(2,3) loop, which provides precise positioning of an invariant arginine from the PBC, and 4) a conserved structural element consisting of an N-terminal helix, an eight residue loop and the A-helix (N3A-motif). The PBC and the hinge were included in the previously reported allosteric model, whereas the definition of the beta(2,3) loop and the N3A-motif as conserved elements is novel. The N3A-motif is found in all cis-regulated CNB domains, and we present a model for an allosteric mechanism in these domains. Catabolite gene activator protein (CAP) represents a trans-regulated CNB domain family: it does not contain the N3A-motif, and its long range allosteric interactions are substantially different from the cis-regulated CNB domains.