Charcot–Marie–Tooth disease-associated mutant tRNA synthetases linked to altered dimer interface and neurite distribution defect
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- Leslie A. Nangle
- The Skaggs Institute for Chemical Biology and the Department of Molecular Biology, The Scripps Research Institute, BCC-379, 10550 North Torrey Pines Road, La Jolla, CA 92037
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- Wei Zhang
- The Skaggs Institute for Chemical Biology and the Department of Molecular Biology, The Scripps Research Institute, BCC-379, 10550 North Torrey Pines Road, La Jolla, CA 92037
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- Wei Xie
- The Skaggs Institute for Chemical Biology and the Department of Molecular Biology, The Scripps Research Institute, BCC-379, 10550 North Torrey Pines Road, La Jolla, CA 92037
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- Xiang-Lei Yang
- The Skaggs Institute for Chemical Biology and the Department of Molecular Biology, The Scripps Research Institute, BCC-379, 10550 North Torrey Pines Road, La Jolla, CA 92037
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- Paul Schimmel
- The Skaggs Institute for Chemical Biology and the Department of Molecular Biology, The Scripps Research Institute, BCC-379, 10550 North Torrey Pines Road, La Jolla, CA 92037
書誌事項
- 公開日
- 2007-07-03
- DOI
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- 10.1073/pnas.0705055104
- 公開者
- Proceedings of the National Academy of Sciences
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説明
<jats:p> Charcot–Marie–Tooth (CMT) diseases are the most common heritable peripheral neuropathy. At least 10 different mutant alleles of <jats:italic>GARS</jats:italic> (the gene for glycyl-tRNA synthetase) have been reported to cause a dominant axonal form of CMT (type 2D). 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 aminoacylation 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. </jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 104 (27), 11239-11244, 2007-07-03
Proceedings of the National Academy of Sciences