EMBO Conference on Protein Synthesis and Translational Control

<strong>EMBO</strong> <strong>Conference</strong> on Protein Synthesis and Translational Control
EMBL Heidelberg, 9-13 September 2009
WILLIAM MERRICK
Possible mechanism of regulation of IRES-mediated expression by eIF2A
William Merrick, Yu Cao, Lucas Reineke, Diane Baus
Case Western Reserve University, United States of America
We have previously shown that eIF2A has the capability of repressing expression from the
URE2 IRES in vivo by use of a knock out strain of yeast.1 Current studies have been
addressing how this down regulation might be achieved. There are now five pieces of evidence
that allow for the postulation of a model for this regulation: 1. the eIF2A mRNA disappears
within 2-3 minutes with essentially any stress 2. eIF2A protein may or may not show enhanced
degradation depending on the stress 3. eEF1A binds to the URE2 IRES element 4. by pull
down experiments, eEF1A and eIF2A reciprocally bind each other (although each also pulls
down several other proteins) 5. it appears that the interaction between eEF1A and eIF2A is
through the C-terminal regions of each protein In the model to be presented, it is anticipated
that the binding of eEF1A to the URE2 IRES-element facilitates the binding of eIF2A (and
Met-tRNA) and that the resulting complex at the level of the 80S ribosome is slow to convert to
an elongating ribosome With the down-regulation of eIF2A protein and/or activity, eIF2 is
presumed to direct Met-tRNA binding in a manner that is much more efficient allowing for a
10-fold increase in expression from this IRES element. Finally, we have preliminary evidence
that the regulation of IRES-mediated expression is not exclusive to the URE2 IRES element but
that eIF2A down-regulates expression from several other IRES elements as well. However, for
most of the IRES elements with poly(A) stretches 5’ of the initiating AUG (identified by Gilbert et
al.2), there appears to be no regulation by eIF2A. 1. Komar, A. A., Gross, S. R., Barth-Baus,
D., Strachan, R., Hensold, J. O., Kinzy, T. G. and Merrick, W. C., J. Biol. Chem. 280,
15601-15611, 2005. 2. Gilbert, W. V., Zhou, K., Butler, T. K. and Doudna, J. A., Science 317,
1224-1227, 2007.
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