Xie Wei, Nangle Leslie A, Zhang Wei, Schimmel Paul, Yang Xiang-Lei
The Skaggs Institute for Chemical Biology and Department of Molecular Biology, The Scripps Research Institute, BCC-379, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):9976-81. doi: 10.1073/pnas.0703908104. Epub 2007 Jun 1.
Functional expansion of specific tRNA synthetases in higher organisms is well documented. These additional functions may explain why dominant mutations in glycyl-tRNA synthetase (GlyRS) and tyrosyl-tRNA synthetase cause Charcot-Marie-Tooth (CMT) disease, the most common heritable disease of the peripheral nervous system. At least 10 disease-causing mutant alleles of GlyRS have been annotated. These mutations scatter broadly across the primary sequence and have no apparent unifying connection. Here we report the structure of wild type and a CMT-causing mutant (G526R) of homodimeric human GlyRS. The mutation is at the site for synthesis of glycyl-adenylate, but the rest of the two structures are closely similar. Significantly, the mutant form diffracts to a higher resolution and has a greater dimer interface. The extra dimer interactions are located approximately 30 A away from the G526R mutation. Direct experiments confirm the tighter dimer interaction of the G526R protein. The results suggest the possible importance of subtle, long-range structural effects of CMT-causing mutations at the dimer interface. From analysis of a third crystal, an appended motif, found in higher eukaryote GlyRSs, seems not to have a role in these long-range effects.
特定tRNA合成酶在高等生物中的功能扩展已有充分记录。这些额外的功能或许可以解释为何甘氨酰-tRNA合成酶（GlyRS）和酪氨酰-tRNA合成酶中的显性突变会导致夏科-马里-图斯病（CMT），这是周围神经系统最常见的遗传性疾病。至少已注释了10个导致疾病的GlyRS突变等位基因。这些突变广泛分布于一级序列中，且没有明显的统一联系。在此，我们报告了同二聚体人GlyRS野生型和一个导致CMT的突变体（G526R）的结构。该突变位于甘氨酰-腺苷酸合成位点，但这两种结构的其余部分非常相似。值得注意的是，突变体形式的衍射分辨率更高，且具有更大的二聚体界面。额外的二聚体相互作用位于距G526R突变约30埃处。直接实验证实了G526R蛋白的二聚体相互作用更强。结果表明，在二聚体界面处导致CMT的突变产生的微妙远程结构效应可能具有重要意义。通过对第三块晶体的分析，在高等真核生物GlyRS中发现的一个附加基序似乎在这些远程效应中不起作用。
