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Konitsiotis A.D.,Max Planck Institute of Molecular Physiology | Jovanovic B.,Imperial College London | Ciepla P.,Sir Alexander Fleming Building | Ciepla P.,Imperial College London | And 5 more authors.
Journal of Biological Chemistry | Year: 2015

Background: Hedgehog acyltransferase (HHAT) palmitoylates hedgehog proteins and is a potential target in cancer. Results: HHAT has ten transmembrane domains, two reentrant loops, and four palmitoylation sites. Conclusion: HHAT topology is determined, and protein is multipalmitoylated, which modulates protein function. Significance: Elucidating HHAT topology and posttranslational modifications is crucial to understand its acyltransferase activity and to develop new strategies to treat cancer. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Grippon S.,Sir Alexander Fleming Building | Zhao Q.,Sir Alexander Fleming Building | Robinson T.,Imperial College London | Marshall J.J.T.,Imperial College London | And 8 more authors.
Nucleic Acids Research | Year: 2011

Mismatch uracil DNA glycosylase (Mug) from Escherichia coli is an initiating enzyme in the base-excision repair pathway. As with other DNA glycosylases, the abasic product is potentially more harmful than the initial lesion. Since Mug is known to bind its product tightly, inhibiting enzyme turnover, understanding how Mug binds DNA is of significance when considering how Mug interacts with downstream enzymes in the base-excision repair pathway. We have demonstrated differential binding modes of Mug between its substrate and abasic DNA product using both band shift and fluorescence anisotropy assays. Mug binds its product cooperatively, and a stoichiometric analysis of DNA binding, catalytic activity and salt-dependence indicates that dimer formation is of functional significance in both catalytic activity and product binding. This is the first report of cooperativity in the uracil DNA glycosylase superfamily of enzymes, and forms the basis of product inhibition in Mug. It therefore provides a new perspective on abasic site protection and the findings are discussed in the context of downstream lesion processing and enzyme communication in the base excision repair pathway. © 2011 The Author(s).

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