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Chris S. Fraser
The overall goal of my research is to understand how the mammalian
translation initiation factor eIF3 contributes to the mechanism and
regulation of mRNA translation. The mammalian factor possesses a molecular
mass of about 700-kDa and contains at least 12 nonidentical protein
subunits. Specific functions for mammalian eIF3 have been identified by a
variety of in vitro experiments. It binds directly to 40S ribosomal
subunits in the absence of other initiation components, and affects the
association/dissociation of ribosomes. It promotes the binding of Met-tRNAi
and mRNA to the 40S ribosomal subunit, and binds directly to eIF1, eIF4B,
eIF4G and eIF5. Clearly, eIF3 plays a central role in the initiation
pathway, perhaps structurally organizing other translational components on
the surface of the 40S ribosomal subunit. The great challenge ahead is to
obtain detailed structural data of the eIF3 complex and to ultimately study
this factor bound to the ribosome using co-crystal structures and cryo-electron
microscopy studies.
My experimental strategy has been: (1) to reconstitute eIF3 subcomplexes
using the baculovirus expression system and to investigate the functions
of these complexes by testing them for the known eIF3 functions in
vitro; (2) to determine high-resolution structures of human eIF3
and/or its subcomplexes by X-ray crystallography; and (3) to study how
eIF3 activity may be modulated by covalent modification of its subunits.
Selected Publications
Fraser, C.S. and Doudna, J.A. (2007)
Quantitative studies of ribosome conformational dynamics.
Q Rev Biophys. 40, 163-189.
(308KB .pdf)
Fraser, C.S., Berry, K.E., Hershey, J.W. and Doudna, J.A. (2007)
eIF3j is located in the decoding center of the human 40S ribosomal subunit.
Mol. Cell. 26, 811-819.
(1.4MB .pdf)
Damoc, E., Fraser, C.S., Zhou, M., Videler, H., Mayeur, G.L.,
Hershey, J.W., Doudna, J.A., Robinson, C.V. and Leary, J.A. (2007)
Structural characterization of the human eukaryotic initiation factor 3 protein complex by mass spectrometry.
Mol. Cell. Proteomics. 6, 1135-1146. Epub 2007 Feb 23.
(604KB .pdf)
Fraser, C.S. and Doudna, J.A. (2007)
Structural and mechanistic insights into hepatitis C viral translation initiation.
Nat. Rev. Microbiol. 5, 29-38.
(680KB .pdf)
Siridechadilok, B., Fraser, C.S., Hall, R.J., Doudna, J.A. and Nogales, E. (2005)
Structural roles for human translation factor eIF3 in initiation of protein synthesis.
Science 310, 1513-1515.
(216KB .pdf)
(Supplemental material: 712KB .pdf)
(Figure and QuickTime Movies)
(Structures)
Ji, H., Fraser, C.S., Yu, Y., Leary, J. and Doudna, J.A. (2004)
Coordinated assembly of human translation initiation complexes by the
hepatitis C virus internal ribosome entry site RNA.
PNAS 101, 16990-16995.
(508KB PDF)
(Figure)
Fraser, C.S., Lee, J.Y., Mayeur, G.L., Bushell, M.,
Doudna, J.A. and Hershey, J.W. (2003) The j-subunit of human translation initiation factor
eIF3 is required for the stable binding of eIF3 and its subcomplexes to
40S ribosomal subunits in vitro. J. Biol. Chem. 279, 8946-8956.
(532KB PDF)
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