Molecular Mechanisms of Eukaryotic Translation Initiation and its Regulation:
Control of protein synthesis (translation) is vital for cell proliferation and differentiation. Initiation of translation is typically rate-limiting and is the main target of regulation. In cancer cells, multiple components of the translation initiation machinery are up-regulated in response to the demand for high rates of protein synthesis. The potential of using inhibitors of translation initiation for anti-cancer therapy was demonstrated in recent years and currently presents an active area of research.
Translation initiation is the process of locating the correct translation start codon on the mRNA and the assembly of an active ribosome, ready for translation. It requires a number of eukaryotic translation initiation factors (eIFs) and consists of several steps: initiation complex assembly; binding to mRNA; scanning; start codon recognition; and finally joining of the large ribosomal subunit to form a ribosome with a bound initiator Met-tRNAi ready to translate the mRNA. The initiator Met-tRNAi is delivered to the ribosome as a complex with eIF2-GTP. One eIF2-GTP:Met-tRNAi complex is “consumed” in every translation initiation cycle, with release of eIF2-GDP and deacylated initiator tRNAi. Regeneration of the eIF2-GTP:Met-tRNAi complex from eIF2-GDP and Met-tRNAi is catalyzed by the nucleotide exchange factor (GEF) eIF2B (reviewed in Marintchev and Wagner, 2004).
Our work is focused on studying the architecture of the translation initiation complexes, the molecular mechanisms of key steps in the process, and their regulation. The long-term goal is to build a detailed mechanistic and quantitative model of translation initiation as a whole, and learn how to rationally manipulate the system for the purposes of cancer therapy and treatment of metabolic disorders. Two areas of particular interest are the coordination between start codon selection and ribosomal subunit joining, and the regeneration of the eIF2-GTP:Met-tRNAi complex.
- University of Connecticut, PhD
- Sofia University, MS
- Sofia University, BS
- Published on 11/16/2017
Bogorad AM, Lin KY, Marintchev A. Novel mechanisms of eIF2B action and regulation by eIF2a phosphorylation. Nucleic Acids Res. 2017 Nov 16; 45(20):11962-11979. PMID: 29036434.
- Published on 6/20/2016
Nag N, Lin KY, Edmonds KA, Yu J, Nadkarni D, Marintcheva B, Marintchev A. eIF1A/eIF5B interaction network and its functions in translation initiation complex assembly and remodeling. Nucleic Acids Res. 2016 Sep 06; 44(15):7441-56. PMID: 27325746.
- Published on 5/20/2014
Bogorad AM, Xia B, Sandor DG, Mamonov AB, Cafarella TR, Jehle S, Vajda S, Kozakov D, Marintchev A. Insights into the architecture of the eIF2Ba/ß/d regulatory subcomplex. Biochemistry. 2014 Jun 3; 53(21):3432-45. PMID: 24811713.
- Published on 1/19/2013
Marintchev A. Roles of helicases in translation initiation: a mechanistic view. Biochim Biophys Acta. 2013 Aug; 1829(8):799-809. PMID: 23337854.
- Published on 1/1/2013
Marintchev, A. In: Dinman, J.D. (Ed.) Biophysical approaches to translational control of gene expression. Methods for studying the interactions of translation factors with the ribosome. Springer. New York, NY. 2013; 1:pp 83-101.
- Published on 5/24/2012
Luna RE, Arthanari H, Hiraishi H, Nanda J, Martin-Marcos P, Markus MA, Akabayov B, Milbradt AG, Luna LE, Seo HC, Hyberts SG, Fahmy A, Reibarkh M, Miles D, Hagner PR, O'Day EM, Yi T, Marintchev A, Hinnebusch AG, Lorsch JR, Asano K, Wagner G. The C-terminal domain of eukaryotic initiation factor 5 promotes start codon recognition by its dynamic interplay with eIF1 and eIF2ß. Cell Rep. 2012 Jun 28; 1(6):689-702. PMID: 22813744.
- Published on 1/1/2012
Marintchev A. Fidelity and quality control in gene expression. Preface. Adv Protein Chem Struct Biol. 2012; 86:ix. PMID: 22243586.
- Published on 2/8/2011
Yu Y, Abaeva IS, Marintchev A, Pestova TV, Hellen CU. Common conformational changes induced in type 2 picornavirus IRESs by cognate trans-acting factors. Nucleic Acids Res. 2011 Jun; 39(11):4851-65. PMID: 21306989.
- Published on 11/26/2010
Abaeva IS, Marintchev A, Pisareva VP, Hellen CU, Pestova TV. Bypassing of stems versus linear base-by-base inspection of mammalian mRNAs during ribosomal scanning. EMBO J. 2011 Jan 5; 30(1):115-29. PMID: 21113134.
- Published on 6/26/2009
Yu Y, Marintchev A, Kolupaeva VG, Unbehaun A, Veryasova T, Lai SC, Hong P, Wagner G, Hellen CU, Pestova TV. Position of eukaryotic translation initiation factor eIF1A on the 40S ribosomal subunit mapped by directed hydroxyl radical probing. Nucleic Acids Res. 2009 Aug; 37(15):5167-82. PMID: 19561193.
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