Structures of parasitic CDPK domains point to a common mechanism of activation
Structures of parasitic CDPK domains point to a common mechanism of activation
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DOI：
10.1002/prot.22919
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发表时间：
2011-03-01
影响因子：
2.9
通讯作者：
Hui, Raymond
中科院分区：
文献类型：
--
作者：
Wernimont, Amy K.;Amani, Merhnaz;Hui, Raymond
我们最近确定了顶复合体中失活和钙活化的钙依赖性蛋白激酶（CDPKs）的第一个结构。钙结合引发了巨大的构象变化，构成了钙信号传导的新机制和一种新的EF-hand折叠（CAD，即CDPK激活域）。因此，我们开始确定这种机制是否适用于所有CDPKs。我们解决了额外的CDPK结构，包括一个来自疟原虫的结构。我们强调了顶复合体和植物CDPKs在序列和结构上的相似性，并加强了我们的观察，即这种新机制可能是典型CDPKs的普遍机制。我们的新结构展示了钙活化机制的更详细步骤和可能的调节关键角色。参与最大构象变化的残基在顶络合物中是最保守的，这使我们提出该机制确实是保守的。CpCDPK3_CAD和PfCDPK_CAD在可能的中间构象中被捕获，从而深入了解激活步骤的顺序。PfCDPK3_CAD采用激活折叠，尽管在n端叶有一个不活跃的EF-hand序列。我们提出，对于大多数顶复合体CDPKs，激活模式将与我们在结构中看到的相似，而非活性形式和活性形式的具体调节将需要进一步研究。
We recently determined the first structures of inactivated and calcium-activated calcium-dependent protein kinases (CDPKs) from Apicomplexa. Calcium binding triggered a large conformational change that constituted a new mechanism in calcium signaling and a novel EF-hand fold (CAD, for CDPK activation domain). Thus we set out to determine if this mechanism was universal to all CDPKs. We solved additional CDPK structures, including one from the species Plasmodium. We highlight the similarities in sequence and structure across apicomplexan and plant CDPKs, and strengthen our observations that this novel mechanism could be universal to canonical CDPKs. Our new structures demonstrate more detailed steps in the mechanism of calcium activation and possible key players in regulation. Residues involved in making the largest conformational change are the most conserved across Apicomplexa, leading us to propose that the mechanism is indeed conserved. CpCDPK3_CAD and PfCDPK_CAD were captured at a possible intermediate conformation, lending insight into the order of activation steps. PfCDPK3_CAD adopts an activated fold, despite having an inactive EF-hand sequence in the N-terminal lobe. We propose that for most apicomplexan CDPKs, the mode of activation will be similar to that seen in our structures, while specific regulation of the inactive and active forms will require further investigation.