The Skaggs Institute
for Chemical Biology
Heritable Diseases Associated With
the Translation Apparatus
P. Schimmel, J. Bacher, K. Beebe,
Z. Druzina, K. Ewalt, M. Kapoor, E. Merriman, C. Motta, L. Nangle, F. Otero, J. Reader,
R. Reddy, M. Swairjo, K. Tamura, E. Tzima, W. Waas, X.-L. Yang
information is translated into proteins, starting with a reaction known as aminoacylation. Enzymes
called aminoacyl tRNA synthetases are the catalysts of aminoacylation in all organisms. Altogether
20 different aminoacyl tRNA synthetases are needed to sustain protein synthesis and living systems.
These enzymes are at the center of our investigations. Significantly, recent work in many laboratories
has established a connection between heritable diseases and specific aminoacyl tRNA synthetases.
Understanding this connection and how the diseases themselves might be treated is of current interest.
Charcot-Marie-Tooth disease type 2D and
distal spinal muscular atrophy type V are neurodegenerative diseases. They are characterized
by distal limb weakness and wasting that appears most severe in the upper extremities. Mutations
in the autosomal gene for one of the aminoacyl tRNA synthetases, glycyl-tRNA synthetase, have
been implicated as the cause of the 2 diseases. Importantly, the mutations are dominant; that is,
in a diploid cell with 2 copies of each gene on each chromosome, the mutant allele (or copy) specifies
the production of a glycyl-tRNA synthetase that overrides the activity of the normal, so-called
wild-type copy. This override suggests that the mutant enzyme has gained a new, aberrant activity
that causes the disease phenotype. We are investigating the biochemistry and genetics of the disease-causing
enzyme and are determining the 3-dimensional structure of the wild-type and mutant enzymes. In
parallel with these efforts, we are interested in understanding other proteins in neuronal cells
that might interact with glycyl-tRNA synthetase. Such interactions could give clues as to how
the mutant enzyme causes Charcot-Marie-Tooth disease type 2D or distal spinal muscular atrophy
In a related area, in a mouse model, a neurodegenerative
condition is associated with a single mutation in a different aminoacyl tRNA synthetase. In this
instance, the disease is manifested as ataxia and deterioration of a specific region of the brain.
Detailed biochemical investigations have narrowed down the possibilities for how the mutation
causes neurodegeneration and have suggested what kinds of therapeutic approaches might be deployed.
Last, in a third line of investigation,
we have focused on placing a rationally chosen mutation in the gene for a third aminoacyl tRNA synthetase.
The idea is to test a specific hypothesis of how mutations in these components (aminoacyl tRNA synthetases)
are dominant and lead to disease phenotypes. These studies offer a powerful test of our understanding
of at least one way that specific diseases could be connected to mutations in aminoacyl tRNA synthetases.
Bacher, J.M., de Crécy-Lagard,
V., Schimmel, P. Inhibited cell growth and protein functional
changes from an editing-defective tRNA synthetase. Proc. Natl. Acad. Sci. U. S. A. 102:1697, 2005.
Ewalt, K.L., Schimmel, P. Protein
biosynthesis: tRNA synthetases. In: Encyclopedia of Biological Chemistry. Lennarz,
W.J., Lane, M.D. (Eds.). Academic Press, San Diego, 2004, p. 263.
Ewalt, K.L., Yang, X-L., Otero,
F., Liu, J., Slike, B., Schimmel, P. Variant of human enzyme
sequesters reactive intermediate. Biochemistry 44:4216, 2005.
Metzgar, D., Bacher, J.M., Pezo,
V., Reader, J., Doring, V., Schimmel, P., Marlière, P., de Crécy-Lagard, V. Acinetobacter
sp ADP1: an ideal model organism for genetic analysis and genome engineering. Nucleic Acid Res.
Nordin, B.E., Schimmel, P. Isoleucyl
tRNA synthetase. In: Aminoacyl-tRNA Synthetases. Ibba, M., Francklyn, C., Cusack, S.
(Eds.). Landes Biosciences/Eurekah.com, Georgetown, TX, 2005, p. 24.
Reader, J.S., Ordoukhanian, P.T.,
Kim, J.-G., de Crécy Lagard, V., Hwang, I., Farrand, S., Schimmel, P. Major
biocontrol of plant tumors targets tRNA synthetase [published correction appears in Science.
310:54, 2005]. Science 309:1533, 2005.
Ribas de Pouplana, L., Musier-Forsyth,
K., Schimmel, P. Alanyl-tRNA synthetases. In: Aminoacyl-tRNA
Synthetases. Ibba, M., Francklyn, C., Cusack, S. (Eds.). Landes Biosciences/Eurekah.com, Georgetown,
TX, 2005, p. 241.
Ribas de Pouplana, L., Schimmel, P. Aminoacylations of tRNAs: record-keepers for the genetic
code. In: Protein Synthesis and Ribosome Structure: Translating the Genome. Nierhaus,
K.H., Wilson, D.N. (Eds.). Wiley-VCH, New York, 2004, p. 169.
Schimmel, P., Beebe, K. From the RNA world to the theater of proteins. In: The RNA World, 3rd ed. Gesteland, R.R., Cech,
T.R., Atkins, J.F. (Eds.). Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, in
Schimmel, P., Ewalt, K. Translation silenced by fused pair of tRNA synthetases. Cell 119:147, 2004.
Schimmel, P., Söll, D. The world of aminoacyl-tRNA synthetases. In: Aminoacyl-tRNA Synthetases. Ibba, M., Francklyn,
C., Cusack, S. (Eds.). Landes Biosciences/Eurekah.com, Georgetown, TX, 2005, p. 1.
M.A., Schimmel, P . Breaking sieve for steric exclusion of
a noncognate amino acid from active site of a tRNA synthetase. Proc. Natl. Acad. Sci. U. S. A. 102:988,
Tamura, K., Schimmel, P.
Non-enzymatic aminoacylation of an RNA minihelix with an aminoacyl phosphate oligonucleotide.
Nucleic Acids Symp. Ser. 48:269, 2004.
Tzima, E., Reader, J.S., Irani-Tehrani,
M., Ewalt, K.L., Schwartz, M.A., Schimmel, P. VE-cadherin
links tRNA synthetase cytokine to anti-angiogenic function. J. Biol. Chem. 280: 405, 2005.
Tzima, E., Schimmel, P. Inhibition
of tumor angiogenesis by a natural fragment of a tRNA synthetase. Trends Biochem. Sci., in press.
Waas, W.F., de Crécy Lagard,
V., Schimmel, P. Discovery of a gene family critical to wyosine
base formation in a subset of phenylalanine-specific transfer RNAs. J. Biol. Chem. 280:37616,