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Sujata S Jha Thesis .pdf (6.34 MB)

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Elucidating the Role of Non Random Synonymous Codon Usage in Fine Tuning the Process of Co-translational Protein Folding

JHA, SUJATA S
http://rave.ohiolink.edu/etdc/view?acc_num=csu1413375693

Abstract Details

2014, Doctor of Philosophy in Regulatory Biology, Cleveland State University, College of Sciences and Health Professions.
After decades of research, the exact path any polypeptide follows to achieve its functional conformation in vivo is still an enigma. Protein folding in vivo is a co-translational process. It starts early on, during elongation of the nascent polypeptide in the ribosomal exit tunnel and continues immediately after the chain extrudes out of the ribosome. The rate of elongation during translation is non-uniform and altered rate of elongation can ultimately affect the folding dynamics of the elongating nascent polypeptide. One of the factors that predominantly influences the rate of translation elongation, is the non-uniform usage of synonymous codons along the mRNA (codon usage bias). Codon usage bias exists because genetic code is degenerate and certain synonymous codons are used with higher frequency (frequent codons) than others (rare codons). It is well known that the relative abundance of tRNAs responding to frequently used codons is also high, which further implies that a frequent codon will be translated faster by the ribosome than the rare codon. Thus, mRNA not only codes for amino acid sequence of the synthesized polypeptide, but it also governs the rate at which different parts of the polypeptide will appear out of the ribosome, i.e. it contains a kinetic code for ribosome movement and peptide elongation. Recent experiments support the hypothesis that distribution of rare and frequent codons along mRNA is not random, but it is evolutionarily conserved and positioned strategically along mRNA to influence the rate of translation elongation. This rate fine tunes the co-translational folding, by allowing temporal and spatial separation of different folding events. We have designed synonymous variants of Bovine Gamma-B Crystallin gene that encode proteins with identical amino acid sequences but altered codon usage and expressed them in in vivo in E. coli and in vitro in various cell-free extracts. These variants were designed and used to comprehensively test the role of synonymous codon usage on 1) protein expression 2) kinetics of translation elongation and ultimately on 3) co-translational protein folding. We provide evidence showing that relative distribution of rare and frequent synonymous codons along mRNA plays a pivotal role in dictating translation kinetics and ensures functional and efficient co-translational protein folding. This study for the first time also demonstrates that altered elongation rates affect the conformation of the ribosome bound nascent chains.
Anton Komar , PhD (Advisor)
Crystal Weyman, PhD (Committee Member)
Barsanjit Mazumder, PhD (Committee Member)
Jun Qin, PhD (Committee Member)
Girish Shukla, PhD (Other)
Saurav Misra, PhD (Other)
251 p.
Biology; Molecular Biology

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Citations

  • JHA, S. S. (2014). Elucidating the Role of Non Random Synonymous Codon Usage in Fine Tuning the Process of Co-translational Protein Folding [Doctoral dissertation, Cleveland State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=csu1413375693

    APA Style (7th edition)

  • JHA, SUJATA. Elucidating the Role of Non Random Synonymous Codon Usage in Fine Tuning the Process of Co-translational Protein Folding. 2014. Cleveland State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=csu1413375693.

    MLA Style (8th edition)

  • JHA, SUJATA. "Elucidating the Role of Non Random Synonymous Codon Usage in Fine Tuning the Process of Co-translational Protein Folding." Doctoral dissertation, Cleveland State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=csu1413375693

    Chicago Manual of Style (17th edition)

csu1413375693
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© 2014, all rights reserved.
This open access ETD is published by Cleveland State University and OhioLINK.