CMT disease-associated mutant tRNA synthetases linked to altered dimer interface

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Proc Natl Acad Sci U S A. 2007 Jun 26

Charcot-Marie-Tooth disease-associated mutant tRNA synthetases

linked to altered dimer interface and neurite distribution defect.

Nangle LA, Zhang W, Xie W, Yang XL, Schimmel P.

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.

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. H

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.