IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis
IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis
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DOI：
10.1093/hmg/ddg147
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发表时间：
2003-06-15
影响因子：
3.5
通讯作者：
Chelly, J
中科院分区：
文献类型：
--
作者：
Bahi, N;Friocourt, G;Chelly, J
以前，基于人类遗传学的方法使我们能够证明IL-1受体辅助蛋白样基因（IL 1 RAPL）的突变是导致X连锁精神发育迟滞的非特异性形式的原因。该基因编码属于IL-1/Toll受体家族的新类别的696个氨基酸的预测蛋白。除了由三个Ig样结构域组成的胞外部分和IL-1/Toll受体家族特有的胞内TIR结构域之外，IL 1 RAPL还含有与任何已知功能的蛋白质没有显著同源性的特异性150个氨基酸的羧基末端。为了开始阐明这种IL-1/Toll受体样蛋白的功能，我们评估了重组IL 1 RAPL对I型IL-1 R与其配体IL-1 a和B的结合亲和力的影响，并寻找与IL 1 RAPL的特异性羧基末端结构域相互作用的蛋白。我们的结果表明，IL 1 RAPL不是IL-1的蛋白受体。此外，我们在这里提出的鉴定神经元钙传感器-1（NCS-1）作为IL 1 RAPL相互作用。值得注意的是，虽然NCS-1和它的非哺乳动物同源物，frequenin，是一个高度保守的EF-手Ca 2+结合蛋白家族的成员，我们的数据显示，IL 1 RAPL仅通过其特定的C-末端结构域与NCS-1相互作用。对过表达IL 1 RAPL的PC 12细胞中胞吐作用的抑制作用进一步支持了IL 1 RAPL活性的功能相关性。两者合计，我们的数据表明，IL 1 RAPL可以调节钙依赖性胞吐作用，并提供深入了解的生理病理机制的认知功能障碍导致IL 1 RAPL功能障碍。
Previously, human genetics-based approaches allowed us to show that mutations in the IL-1 receptor accessory protein-like gene (IL1RAPL) are responsible for a non-specific form of X-linked mental retardation. This gene encodes a predicted protein of 696 amino acids that belongs to a novel class of the IL-1/Toll receptor family. In addition to the extracellular portion consisting of three Ig-like domains and the intracellular TIR domain characteristic of the IL-1/Toll receptor family, IL1RAPL contains a specific 150 amino acid carboxy terminus that has no significant homology with any protein of known function. In order to begin to elucidate the function of this IL-1/Toll receptor-like protein, we have assessed the effect of recombinant IL1RAPL on the binding affinity of type I IL-1R for its ligands IL-1a and b and searched for proteins interacting with the specific carboxy terminus domain of IL1RAPL. Our results show that IL1RAPL is not a protein receptor for IL-1. In addition we present here the identification of Neuronal Calcium Sensor-1 (NCS-1) as an IL1RAPL interactor. Remarkably, although NCS-1 and its non-mammalian homologue, frequenin, are members of a highly conserved EF-hand Ca2+ binding protein family, our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. Taken together, our data suggest that IL1RAPL may regulate calcium-dependent exocytosis and provide insight into the understanding of physiopathological mechanisms underlying cognitive impairment resulting from IL1RAPL dysfunction.