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Abstract：
Neuronal calcium sensor-1 (NCS-1) is a Ca(2+) sensor protein that has been implicated in the regulation of various aspects of neuronal development and neurotransmission. It exerts its effects through interactions with a range of target proteins one of which is interleukin receptor accessory protein like-1 (IL1RAPL1) protein. Mutations in IL1RAPL1 have recently been associated with autism spectrum disorders and a missense mutation (R102Q) on NCS-1 has been found in one individual with autism. We have examined the effect of this mutation on the structure and function of NCS-1. From use of NMR spectroscopy, it appeared that the R102Q affected the structure of the protein particularly with an increase in the extent of conformational exchange in the C-terminus of the protein. Despite this change NCS-1(R102Q) did not show changes in its affinity for Ca(2+) or binding to IL1RAPL1 and its intracellular localisation was unaffected. Assessment of NCS-1 dynamics indicated that it could rapidly cycle between cytosolic and membrane pools and that the cycling onto the plasma membrane was specifically changed in NCS-1(R102Q) with the loss of a Ca(2+) -dependent component. From these data we speculate that impairment of the normal cycling of NCS-1 by the R102Q mutation could have subtle effects on neuronal signalling and physiology in the developing and adult brain.
摘要：
神经元钙传感器-1（NCS-1）是一种Ca（2）传感器蛋白，与神经元发育和神经传递的各个方面的调节有关。它通过与一系列靶蛋白的相互作用发挥其作用，其中之一是白介素受体辅助蛋白样1（IL1RAPL1）蛋白。最近，IL1RAPL1的突变与自闭症谱系障碍有关，并且在一个自闭症患者中发现了NCS-1上的错义突变（R102Q）。我们已经检查了该突变对NCS-1的结构和功能的影响。从使用核磁共振波谱，似乎R102Q会影响蛋白质的结构，特别是随着蛋白质C末端构象交换程度的增加。尽管发生了这种变化，但NCS-1（R102Q）对Ca（2）的亲和力或与IL1RAPL1的结合并未显示出变化，并且其胞内定位未受影响。对NCS-1动力学的评估表明，它可以在胞质和膜池之间快速循环，并且在NCS-1（R102Q）中，质膜上的循环发生了特定变化，并失去了Ca（2）依赖性成分。根据这些数据，我们推测R102Q突变对NCS-1正常循环的损害可能对发育中和成年大脑中的神经元信号传导和生理学产生微妙影响。
