Laboratories

Laboratory of Molecular Genetics Recruiting students for the academic year 2018

Professor Koichi ITO
+81-4-7136-3600
E-mail: itokoichi{at}k.u-tokyo.ac.jp
Lab HP

Introduction

【Key Words】tRNA mimicry protein, mRNA quality control, genetic switch, yeast prion, genetic decoding

 Cells are composed of a number of biomolecular complexes and their networks. However, molecular details for their regulatory mechanism remain unknown. We seek to identify key molecular events and functions in celluar biological systems by molecular genetic approaches for microorganisms (e.g. Escherichia coli, Saccharomyces cerevisiae) combined with other tecniques.
 Reaserch in our laboratory is focused on the protein sysnthesis apparatus, such as translation termination factors and mRNA quality control (mRNA surveillance) factors, as well as yeast epigenetic prion protein systems and membrane transporter systems.


Decoding mechanism of the stop codons and its versatile functions

 The mechanism of translation termination has long been a puzzle. The polypeptide-chain release factor (RF) plays a key role in terminating protein synthesis. Bacteria have two codon specific RFs, RF1 and RF2, to decipher three stop codons. Decades ago, an idea was formulated that RFs may be protein analogs of tRNA. This idea gained substantial support ten years ago by the identification of two classes of crucial RF peptide motifs, Peptide-anticodon and GGQ, in bacteria. These motifs are functionally equivalent to the anticodon and aminoacyl-CCA terminus of tRNA, although they are involved in different step of translation. In eularyotes translation termination is catalyzed by two class of proteins, eRF1 and eRF3. eRF1 recognizes stop codons and hydrolyzes peptidyl-tRNA as a tRNA mimic, while eRF3, an elongation factor 1α (EF-1α) homolog, binds to and stimulates the activity of eRF1. The roles of stop codons are known to be versatile. A number of essential genes with a premature stop codon in their protein coding regions are expressed by bypassing translation termination using the Sec (Selenocystein) insertion, translational frameshifting and so on. Such mechanisms are called translational RECODING (= Reprogrammed genetic decoding). Moreover, in eukaryotes, the premature stop codons in aberrant mRNAs are recognized differently from normal stop codons and trigger the NMD (= Nonsense mediated mRNA decay) system to avoid harmful protein synthesis. The tRNA mimicry proteins provide a clue to elucidate the mechanism of stop codon recognition.


The ribosome function and the tRNA mimicry protein complexes

 Two homologs of EF1α in eukaryotes form complexes with protein factors mimicking the structure and function of tRNA, rather than with genuine tRNAs. One of the homologs, the class 2 eukaryotic release factor (eRF3) forms a complex with the class 1 eukaryotic release factor (eRF1), which mimics tRNA’s functional as well as structural aspects to catalyze the decoding of stop codons in a way similar to tRNAs. The other homolog, HBS1 forms a complex with Dom34 (Pelota), which is partly homologous to eRF1. The HBS1–Dom34 complex resembles the EF1α-tRNA complex in appearance, and this complex is thought to function in mRNA surveillance or mRNA quality control. However, precise molecular mechanism underlying this putative function is not well understood. Our recent studies have revealed that archaeal EF1α functions as a versatile carrier protein for tRNA and tRNA-like protein adaptors.




Referrences
Cell, 101 :349-352 (2000)*
Nature, 403 :680-684 (2000)
Mol Cell 9 :1263-1272 (2002)
Proc Natl Acad Sci USA 99 :8494-9499 (2002)
WIREs RNA, 2: 647-668 (2011)*
Nucleic Acids Res. 42: 7851-66 (2014)
Nat. Comm. 6:7097 (2015)
Nucleic Acids Res. 43: 4591–601 (2015)
PLoS Genet 11(4): e1005197
Scientific Reports 6 (29295) (2016)
Cell Research 26 (12), 1288-1301 (2016)
*review articles

Laboratories

The University of Tokyo
Graduate School of Frontier Sciences, The University of Tokyo

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