The lifetime of eukaryotic messenger RNA is highly regulated by elements on both the 5' and 3' ends of the message. Methylated guanine "cap" on the 5' end of a message is critical for nuclear export, protein translation, and stability of a message. The cap structure is so crucial that many viruses hijack cellular caps to direct translation towards nefarious ends. Removal of the cap structure of a mRNA is a highly regulated, irreversible step that sentences a mRNA to destruction by conserved exonucleases, and is the ultimate goal of many mRNA surveillance and degradation pathways. An enzyme known as Dcp2 executes decapping, or removal of the cap. Dcp2 from yeast to humans contains two conserved domains: one at the very N-terminus of the protein known as the regulatory domain, and a second following directly in sequence of the Nudix hydrolase family. While the catalytic domain contains the core Nudix motif necessary and sufficient for removal of mRNA caps, the regulatory domain binds the partner Dcp1 and is required for decapping in vivo. The dynamics, structure, and functional consequences of interactions between these two domains are the focus of this manuscript. In sum, regulation of decapping appears to occur by modulating the interaction between these two domains, which creates or inhibits formation of a composite active site that apposes absolutely conserved and catalytically essential regions on both domains.
|Advisor:||Gross, John D.|
|Commitee:||Agard, David A., Jacobson, Matthew P., Narlikar, Geeta|
|School:||University of California, San Francisco|
|School Location:||United States -- California|
|Source:||DAI-B 73/01, Dissertation Abstracts International|
|Subjects:||Molecular biology, Biochemistry, Biophysics|
|Keywords:||Conformational control, Cpmg, Dcp2, Enzyme kinetics, Eukaryotic mRNA decapping, Mrna decay, Protein dynamics|
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