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The Skaggs Institute
for Chemical Biology


Scientific Report 2006




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.

 

Paul R. Schimmel, Ph.D.
Ernest and Jean Hahn Professor and Chair of Molecular Biology and Chemistry

Schimmel Web Site