title: Charcot-Marie-Tooth disease-associated mutant tRNA synthetases linked to altered dimer interface and neurite distribution defect.
abstract: 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 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.
authors.affiliation: The Skaggs Institute for Chemical Biology and the Department of Molecular Biology, BCC-379, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Nangle
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Xie
authors.forename: Xiang-Lei
authors.initials: XL
authors.lastname: Yang
authors.forename: Paul
authors.initials: P
authors.lastname: Schimmel
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001369:Axons / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D002607:Charcot-Marie-Tooth Disease / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D019281:Dimerization; D006032:Glycine-tRNA Ligase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D009154:Mutation; D016501:Neurites / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D013499:Surface Properties; D014162:Transfection; D014448:Tyrosine-tRNA Ligase / Q000235:genetics
chemical_list: D014448:Tyrosine-tRNA Ligase; D006032:Glycine-tRNA Ligase