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Katie Berry
Translation initiation is the process by which the ribosome binds to and
positions a messenger RNA at the initiation (AUG) codon, a prerequisite for
all protein synthesis. In humans, the small subunit of the ribosome
interacts with numerous protein and nucleic acid ligands before joining with
the large subunit to initiate peptide bond catalysis. While many of the
molecular players have been elucidated over the past forty years, relatively
little is known about the kinetics and molecular mechanism of how the
ribosome recruits mRNA, scans to and recognizes the start codon.
Understanding the details of how factors control access and assembly of
ribosomes at the right site on mRNA will illuminate the mechanisms of
translation initiation and enhance our understanding of how the efficiency,
fidelity, and regulation of protein synthesis are achieved.
Recent work in the lab has been geared toward developing a reconstituted
mammalian system consisting of purified human factors with which we can
build preinitiation complexes in vitro, introduce mutant or labeled
components, and precisely control which factors are present and at what
concentrations. Using this system and a combination of fluorescence
spectroscopy and other biochemical techniques, I will quantitatively
analyze the mechanism and kinetics of this complex assembly process,
focusing at first on factors that bind at the mRNA binding cleft of the 40S
ribosome.
In addition to the canonical cap-dependent translation, I am also interested
in the particular mechanisms of translation initiation of messages with
internal ribosome entry sites (IRESs), such as that from the Hepatitis C Virus.
I will use fluorescence techniques to screen for small molecule inhibitors
of HCV IRES, that will then be used in structural and biochemical studies of the
mechanism of this IRES, and potentially lead to new drugs for Hepatitis C,
which infects 1 in 40 people worldwide.
Selected Publications
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)
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