Regulation of translation initiation allows rapid and precise changes in gene expression in response to changing cellular and external conditions. I am interested in the molecular switches that mediate these changes, and how disruptions to translational control lead to unwanted cellular phenotypes. To gain insights into these processes, my lab has been investigating the eIF4 group of translation initiation factors that bind to the 5’ end of mRNAs to allow ribosome loading and scanning. We explore their basic molecular mechanisms, how they are modified in response to stress and cellular changes, and how their dysregulation affects translation, mRNA control, and resulting phenotypes. We employ directed biochemical and genetic techniques, and global surveys of changes in translation in yeast and mammalian cells.
Recent work from the lab has revealed posttranslational modifications of the essential and well-conserved DEAD-box RNA helicase eIF4A that can enhance or rapidly repress translation in yeast cells, dysregulation of eIF4B associated with enhanced metastatic growth of breast cancer cells, and linked a ribosome-binding domain of eIF4B to the ability to translate long, structured mRNAs thought to promote cellular stress responses.
- Liu X, Moshiri H, He Q, Sahoo A, Walker SE. Deletion of the N-Terminal Domain of Yeast Eukaryotic Initiation Factor 4B Reprograms Translation and Reduces Growth in Urea. Front Mol Biosci. 2021; 8:787781. PubMed PMID: 35047555.
- Sahoo, A., He, Q. and Walker, S.E. Flipping the switch: an unexpected role for aEF1B in modulating aEF1A interactions with the ribosome and tRNA. Journal of Molecular Biology. 2021; 433(15):167052. PubMed PMID: 34015279 (Commentary)
- Bowitch, A., Sahoo, A., Clark, A.M., Ntangka, C., Raut, K.K., Gollnick, P., Yu, M.C., Pascal, S.M., Walker, S.E., and Ferkey, D.M. 2021. Methylation of the D2 dopamine receptor affects binding with the human regulatory proteins Par-4 and Calmodulin. MicroPubl Biol. doi:10.17912/micropub.biology.000366.
- Liu, X., Schuessler, P., Sahoo, A., and Walker, S.E. 2019. Reconstitution and Analyses of RNA Interactions with Eukaryotic Translation Initiation Factors and Ribosomal Preinitiation Complexes. Methods. S1046-2023: 30395-5. PMID: 30926531.
- Sehgal, N., Sylves, M.E., Sahoo, A., Chow, J., Walker, S.E., Cullen, P., and Berry, J.O. 2018. CRISPR gene editing in yeast: An experimental protocol for an upper-division undergraduate laboratory course. Biochemistry and Molecular Biology Education; 46(6):592-601.
- Munoz, A.M., Yourik, P., Rajagopal, V., Nanda, J.S., Lorsch, J.R., and Walker, S.E. 2017. Active Yeast Ribosome Preparation Using Monolithic Anion Exchange Chromatography. RNA Biology, 14, 188-196.
- Zhou, F. , Walker, S.E., Mitchell, S.F., Lorsch, J.R., and Hinnebusch, A.G. 2014. Identification and characterization of functionally critical, conserved motifs in the internal repeats and N-terminal domain of yeast translation initiation factor 4B (yeIF4B). Journal of Biological Chemistry, 289, 1704-1722.
- Walker, S.E., Zhou, F. , Mitchell, S.F., Larson, V.S., Valasek, L, Hinnebusch, A.G., and Lorsch, J.R. 2013. Yeast eIF4B binds to the head of the 40S ribosomal subunit and promotes mRNA recruitment through its N-terminal and internal repeat domains. RNA, 19, 191-207
- Park, E.H., Walker, S.E., Zhou, F, Lee, J.M., Rajagopal, V, Lorsch, J.R. and Hinnebusch, A.G. 2013. Yeast Eukaryotic Initiation Factor (eIF) 4B Enhances Complex Assembly between eIF4A and eIF4G in vivo. Journal of Biological Chemistry, 288, 2340-2354.
- Shin, B.S., Kim, J.R., Walker, S.E., Dong, J, Lorsch, J.R., and Dever, T.E. 2011. Initiation factor eIF2g promotes eIF2-GTP-Met-tRNAi(Met) ternary complex binding to the 40S ribosome. Nature Structural and Molecular Biology, 18,1227-1234.
- Park, E.H., Walker, S.E. +, Lee, J.M. +, Rothenburg, S., Lorsch, J.R., and Hinnebusch, A.G. 2011. Multiple elements in the eIF4G1 N-terminus promote assembly of eIF4G1•PABP mRNPs in vivo. EMBO Journal, 30, 302-316.
- Mitchell, S.F., Walker, S.E., Algire, M.A., Park, E.H., Hinnebusch, A.G., and Lorsch, J.R. 2010. The 5´-7-methylguanosine cap on eukaryotic mRNAs serves both to stimulate canonical translation initiation and block an alternative pathway. Molecular Cell, 39: 950-962.
Link to Pubmed Citations, here.