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Exploring induced secondary structure and unmethylated DNA binding domains of methyl CpG binding protein 2 (MeCP2)




Hite, Kristopher Charles, author
Hansen, Jeffrey C., advisor
Woody, Robert W., committee member
Ross, Eric D., committee member
Mykles, Donald L., committee member

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Our understanding of Methyl CpG binding protein 2 (MeCP2) structure and function has changed and expanded considerably over the last two decades. Mutations along the entirety of the human MeCP2 gene product lead to a disease state - Rett syndrome. The clinical connection of this protein has continued to drive intense research into the nature of MeCP2 structure and function. There is now considerable and corroborated evidence that proves MeCP2 is an archetypical intrinsically disordered protein acting as a global ATP independent chromatin architectural protein. The ubiquity of MeCP2 in vertebrate neuronal nuclei has only recently been realized and has focused my investigations. Results from my work demonstrate a clear relationship between predicted α-molecular recognition features and inducible α- helical structure. From these data I suggest that inducible α-helices and maintained intrinsic disorder participate in binding the pool the twenty reported MeCP2 binding partners. In addition to structural studies I have identified two non-specific unmethylated DNA binding domains unreported in the literature at the onset of my work. I have also shown that MeCP2 acquires some secondary structural stability when bound to DNA and relatively little additional stability when bound to methylated DNA. The results presented here improve the fine resolution functional understanding of MeCP2 by observing isolated fragments of MeCP2 using both structural and functional methods. This approach is significant in and of itself as, like the large disordered subset of all eukaryotic proteins, the full-length MeCP2 molecule has proven impossible to crystallize thus far. Therefore narrowing the amino acid residues responsible for DNA binding activity or any other measurable functionality in a solution state is valuable.


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circular dichroism
genetic disease
protein chemistry
Rett Syndrome


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