Structural and Functional Characterization of the Tip60 Chromodomain
Arrafi, Sifa 1988-
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The Tat-interactive protein of 60 kDa (Tip60) is a histone acetyltransferase enzyme that appears to have a wide range of acetylation targets, which include core histone proteins H2A and H4, transcription factors Myc and p53, the androgen receptor, and ATM kinase. Additionally, Tip60 appears to play a role in several cellular processes such as transcriptional regulation, DNA damage repair, chromatin remodeling, and apoptosis. Due to its diverse roles, the deregulation of Tip60 has been implicated in several human diseases, including Alzheimer’s disease and some cancers. Several studies have been conducted in an attempt to elucidate the regulation of Tip60’s acetyltransferase activity. Studies have suggested that the binding of Tip60’s chromodomain to methylated lysine residues found on histone tails is important for targeting substrates and allosterically regulating the enzyme. This research aimed to determine the structure of the chromodomain, identify its binding partners, and elucidate the mechanism of binding. Ultimately, the research aimed to clarify how binding of the chromodomain to its partners would affect acetyltransferase activity. Through x-ray crystallography, the crystal structure of the Drosophila melanogaster Tip60 chromodomain was solved to a resolution of 1.59 Å. The binding partners of the chromodomain were revealed through the use of surface plasmon resonance and confirmed by isothermal titration calorimetry. The binding studies found that the chromodomain preferentially bound peptides, which corresponded to modifications found on the histone H4 N-terminal tail.
DegreeMaster of Science (M.Sc.)
CommitteeLee, Jeremy; Dmitriev, Oleg; Wu, Yuliang
Copyright DateJune 2017