Functional and molecular features of the calmodulin-interacting protein IQCG required for haematopoiesis in zebrafish
Functional and molecular features of the calmodulin-interacting protein IQCG required for haematopoiesis in zebrafish
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斑马鱼造血所需的钙调蛋白相互作用蛋白 IQCG 的功能和分子特征
DOI：
10.1038/ncomms4811
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发表时间：
2014-05-01
影响因子：
16.6
通讯作者：
Chen, Sai-Juan
中科院分区：
文献类型：
--
作者：
Chen, Li-Ting;Liang, Wen-Xue;Chen, Sai-Juan
我们先前报道了急性白血病中的融合蛋白NUP 98-IQCG，其作为转录表达的异常调节因子发挥作用，但IQCG的结构和功能尚未被表征。在这里，我们使用斑马鱼研究iqcg在造血发育中的作用，发现iqcg缺陷胚胎中造血干细胞和多系分化细胞的数量减少。从机制上讲，IQCG与钙调蛋白（CaM）结合，并作为CaM依赖性激酶IV（CaMKIV）上游的分子发挥作用。钙调素和IQCG的IQ结构域之间的复合物的晶体结构揭示了该基序中的双重钙调素结合足迹，并为缺乏钙时更高的钙调素-IQCG亲和力提供了结构基础。这些结果共同使我们能够理解IQCG介导的钙信号在造血，并提出了一个模型，其中IQCG存储钙调素在低细胞质钙浓度，并释放钙调素激活CaMKIV时，钙水平上升。
We previously reported a fusion protein NUP98-IQCG in an acute leukaemia, which functions as an aberrant regulator of transcriptional expression, yet the structure and function of IQCG have not been characterized. Here we use zebrafish to investigate the role of iqcg in haematopoietic development, and find that the numbers of haematopoietic stem cells and multilineage-differentiated cells are reduced in iqcg-deficient embryos. Mechanistically, IQCG binds to calmodulin (CaM) and acts as a molecule upstream of CaM-dependent kinase IV (CaMKIV). Crystal structures of complexes between CaM and IQ domain of IQCG reveal dual CaM-binding footprints in this motif, and provide a structural basis for a higher CaM-IQCG affinity when deprived of calcium. The results collectively allow us to understand IQCG-mediated calcium signalling in haematopoiesis, and propose a model in which IQCG stores CaM at low cytoplasmic calcium concentrations, and releases CaM to activate CaMKIV when calcium level rises.