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The Skaggs Institute
for Chemical Biology
Components of Translation Apparatus as a Cytokine Reservoir Potentially Useful for Human Therapies
P. Schimmel, J. Bacher, K. Beebe, R. Belani, E. Chong, Z. Druzina, P. Fanta, M. Guo, M. Hanan, C. Izutsu, M. Kapoor,
E. Merriman, M. Mock, C. Motta, L.A. Nangle, F.J. Otero, R.R. Reddy, M.A. Swairjo, K. Tamura, W.F. Waas, W. Xie, X.-L. Yang
Cytokines are
cell-signaling proteins required for development and growth of all cell types and
organs found in humans. Specific genes encode many of these proteins. Remarkably,
other proteins, designed to provide the reactions needed to decode, or translate,
genetic information, but not thought to act as cytokines, are themselves empowered
with cytokine activities. These components of the translation apparatus are known
as aminoacyl tRNA synthetases (AARSs). Twenty different AARSs are found in all cell
types. Some of these AARSs are split into pieces and, when split, take on new functions.
Others may act with minor or little such alteration. These cytokine activities are
needed for control of blood vessel growth and inflammation, for example, and probably
for many other functions, including neuronal development.
We
have discovered and characterized 3 AARS-derived cytokines in some detail. This
research has led to the potential for applications to specific abnormalities, including
blindness and oncologic diseases. These applications have been studied in animals
and now being considered for human trials. Currently, we are identifying additional
AARS-derived cytokines and trying to understand how this whole family of cell-signaling
molecules is organized and mobilized. Of particular interest is the complex of AARSs
found in mammalian cells. This complex, which contains many of the 20 AARSs and
some additional AARS-like proteins, is thought to be a reservoir of cytokines that
can be mobilized under specific conditions. Mobilization occurs by dissociation
of a specific AARS from the larger complex; the enzyme is thereby made available
to act in cell signaling.
Thus, a major objective is to understand
the assembly of the complex and the signals needed to trigger dissociation of a
specific AARS from the complex. For this purpose, we are using existing information
about the assembly of the complex from its components to reconstruct partial complexes.
These partial complexes can then be studied by using structural methods, such as
x-ray crystallography. From a more detailed picture of partial complexes, the forces
that bind the partners together can be understood. These forces are the ones that
must be disrupted to dissociate a single AARS from the complex so that the AARS
can go on to execute a cytokine signaling function. At the same time these subcomplexes
are investigated from the structural side, the possibility that specific subcomplexes
themselves have cytokine activities can be investigated. Collectively, these studies
expand the ways to discover novel cell-signaling activities, how they can be manipulated
and controlled, and how they may eventually lead to new therapies.
Publications
Lee, J.W., Beebe, K., Nangle, L.A., Jang, J., Longo-Guess, C.M., Cook, S.A., Davisson, M.T., Sundberg, J.P., Schimmel,
P., Ackerman, S.L. Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration in the sticky mouse.
Nature 443:50, 2006.
Nangle, L., Motta, C.M., Schimmel, P. Global effects of mistranslation from an editing defect in a mammalian cell. Chem. Biol. 13:1091, 2006.
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, 2005, p. 227.
Schimmel, P., Yang, X.L. Perfecting the genetic code with an RNP complex. Structure 14:1729, 2006.
Seburn, K.L., Nangle, L.A., Cox, G.A., Schimmel, P., Burgess, R.W. An active dominant mutant of glycyl-tRNA synthetase causes neuropathy in Charcot-Marie-Tooth
2D mouse model. Neuron 51:715, 2006.
Swairjo, M.A., Reddy, R.R., Lee, B., Van Lanen, S.G., Brown, S., de Crécy-Lagard, V., Iwata-Reuyl, D., Schimmel,
P. Crystallization and preliminary x-ray characterization of the nitrile reductase QueF: a queosine-biosynthesis enzyme.
Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 61(Pt. 10):945, 2005.
Tamura, K., Schimmel, P. Chiral-selective aminoacylation of an RNA minihelix: mechanistic features and chiral suppression.
Proc. Natl. Acad. Sci. U. S. A. 103:13750, 2006. Tzima, E., Schimmel, P. Inhibition
of tumor angiogenesis by a natural fragment of a tRNA synthetase. Trends Biochem. Sci. 31:7, 2006.
Xie, W., Schimmel, P., Yang, X.L. Crystallization and preliminary x-ray analysis of a native human tRNA synthetase
whose allelic variants are associated with Charcot-Marie-Tooth disease. Acta Crystallograph. Sect. F Struct. Biol. Cryst. Commun. 62(Pt. 12):1243, 2006.
Yang, X.-L., Otero, F.J., Ewalt, K.L., Liu, J., Swairjo, M.A., Kohrer, C., RajBhandary, U.L., Skene, R.J., McRee, D.E.,
Schimmel, P. Two conformations of a crystalline human tRNA synthetase-RNA complex: implications for protein synthesis.
EMBO J. 25:2919, 2006.
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