Structural and Functional Characterization of the Tip60 Chromodomain
Date
2016-10-18
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
Type
Thesis
Degree Level
Masters
Abstract
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.
Description
Keywords
Tip60, Chromodomain, Histone, X-ray crystallography, ITC, SPR
Citation
Degree
Master of Science (M.Sc.)
Department
Biochemistry
Program
Biochemistry