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Karin Felderer
Protein synthesis in eukaryotes is a highly regulated
process which is initiated by the binding of small (40S)
ribosomal subunits to initiator Met-tRNAi and mRNA, followed
by association with the large (60S) ribosomal subunit to form
80S ribosomes at the start codon of the mRNA. The assembly of
ordered preinitiation complexes requires the action of several
initiation factors, of which eIF3 is the largest and most
complex, containing 13 nonidentical subunits in humans. Its
multiple functions comprise the inhibition of premature subunit
joining, the stimulation of preinitiation complex assembly
and the recruitment of 5'-capped mRNA via interaction with
eIF4F. Many viral mRNAs bearing an internal ribosome entry site
(IRES) circumvent the need for all or part of the cap binding
complex by directly binding to eIF3.
The goal of my project is to understand how the eukaryotic
initiation factor eIF3 fulfills its functions in both
cap-dependent and cap-independent translation initiation, on a
structural basis. I intend to obtain high-resolution structures
of eIF3 and/or its subunits and subcomplexes using x-ray
crystallography. In parallel I will use cryo-electron microscopy
to investigate eIF3 and its complexes with 40S ribosomal subunits
and the hepatitis C virus IRES at medium resolution. Using
these two techniques in a complementary approach I intend to
obtain detailed knowledge about the mechanisms and interactions
involved in translation initiation at a molecular level.
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