Charcot-Marie-Tooth disease-associated mutant tRNA synthetases linked to altered dimer interface and neurite distribution defect
Charcot-Marie-Tooth disease-associated mutant tRNA synthetases linked to altered dimer interface and neurite distribution defect
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DOI：
10.1073/pnas.0705055104
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发表时间：
2007-07-03
影响因子：
11.1
通讯作者：
Schimmel, Paul
中科院分区：
文献类型：
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作者：
Nangle, Leslie A.;Zhang, Wei;Schimmel, Paul
夏科-玛丽-图斯(Charcot-Marie-Tooth，CMT)病是最常见的遗传性周围神经病。至少有10个GARS(甘氨酰-tRNA合成酶基因)的不同突变等位基因被报道导致显性轴突形式的CMT(213型)。这些突变和CMT之间的统一联系尚不清楚。在这里，将突变映射到最近确定的人类GlyRS的晶体结构上，显示它们位于二聚体界面两侧的一条带内，其中两个导致CMT的突变位于两个位置，这两个点是通过二聚体界面的“接吻”接触的互补伙伴。此处显示CMT表型与氨酰化活性无关。然而，大多数突变会影响二聚体的形成(增强或减弱)。在长出原始神经突起的神经母细胞瘤细胞中，表达了七种引起CMT的突变体和野生型蛋白。野生型GlyRS分布于新生轴突，并与正常轴突萌发有关。相反，所有突变的蛋白质都是分布缺陷的。因此，CMT引起的GlyRS突变在定位上有一个共同的缺陷。这种缺陷可能以某种方式与二聚体界面处表面的变化有关。
Charcot-Marie-Tooth (CMT) diseases are the most common heritable peripheral neuropathy. At least 10 different mutant alleles of GARS (the gene for glycyl-tRNA synthetase) have been reported to cause a dominant axonal form of CMT (type 213). A unifying connection between these mutations and CMT has been unclear. Here, mapping mutations onto the recently determined crystal structure of human GlyRS showed them within a band encompassing both sides of the dimer interface, with two CMT-causing mutations being at sites that are complementary partners of a "kissing" contact across the dimer interface. The CMT phenotype is shown here to not correlate with anninoacylation activity. However, most mutations affect dimer formation (to enhance or weaken). Seven CMT-causing variants and the wild-type protein were expressed in transfected neuroblastoma cells that sprout primitive neurites. Wild-type GlyRS distributed into the nascent neurites and was associated with normal neurite sprouting. In contrast, all mutant proteins were distribution-defective. Thus, CMT-causing mutations of GlyRS share a common defect in localization. This defect may be connected in some way to a change in the surfaces at the dimer interface.