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Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):9976-81. Epub 2007 Jun 1.

Long-range structural effects of a Charcot-Marie-Tooth disease-causing mutation in human glycyl-tRNA synthetase.

Author information

1
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.

Abstract

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.

PMID:
17545306
PMCID:
PMC1891255
DOI:
10.1073/pnas.0703908104
[Indexed for MEDLINE]
Free PMC Article

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