Charcot-Marie-Tooth disease-associated mutant tRNA synthetases linked to altered dimer interface and neurite distribution defect.

Charcot-Marie-Tooth disease-associated mutant tRNA synthetases linked to altered dimer interface and neurite distribution defect. Research Abstract Details 

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Charcot-Marie-Tooth disease-associated mutant tRNA synthetases linked to altered dimer interface and neurite distribution defect. Abstract Text:

Leslie A Nangle,Wei Zhang,Wei Xie,Xiang-Lei Yang,Paul Schimmel,

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.

Charcot-Marie-Tooth disease-associated mutant tRNA synthetases linked to altered dimer interface and neurite distribution defect. Publishing Authors By Initials

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

For similar enzymes and coenzymes: enzymes: ligases: carbon-oxygen ligases: amino acyl-trna synthetases: tyrosine-trna ligase research abstracts see: enzymes and coenzymes: enzymes: ligases: carbon-oxygen ligases: amino acyl-trna synthetases: tyrosine-trna ligase research

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Charcot-Marie-Tooth disease-associated mutant tRNA synthetases linked to altered dimer interface and neurite distribution defect. Journal Published:

PUBLICATION TYPE: Validation Studies

Journal: Proceedings of the National Academy of Sciences of

VOLUME: 104

Page Numbers: 11239-44

Journal Abbreviation: Proc. Natl. Acad. Sci. U.S.A.

ISSN: 0027-8424

DAY: 26

MONTH: 06

YEAR: 2007

Charcot-Marie-Tooth disease-associated mutant tRNA synthetases linked to altered dimer interface and neurite distribution defect. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 7505876

Charcot-Marie-Tooth disease-associated mutant tRNA synthetases linked to altered dimer interface and neurite distribution defect. Keywords Mesh Terms:

KEYWORDS: Tyrosine-tRNA Ligase

MESH TERMS: genetics

Chemical & Substance for Abstract: Charcot-Marie-Tooth disease-associated mutant tRNA synthetases linked to altered dimer interface and neurite distribution defect. Information

Substance Name: Glycine-tRNA Ligase

Registry Number: EC 6.1.1.14

Grant and Affiliation Information for Charcot-Marie-Tooth disease-associated mutant tRNA synthetases linked to altered dimer interface and neurite distribution defect.

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.

Country: United States

AGENCY: United States NIGMS

GRANT: GM23562

ACRONYM: GM

MEDLINETA: Proc Natl Acad Sci U S A

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