With this application, funding is applied for a new project to be started at the Department of Biochemistry, University of Oulu in 2008. The focus of the project will be on structural aspects of protein recognition and regulatory events. To start with, the project will concentrate on selected histone deacetylases and profilins as well as members of the formin family of proteins. X-ray crystallography will be used as the main tool, but the structural work will be complemented by other biochemical and biophysical characterization. Histone deacetylases (HDAC) are, due to their essential role in transcriptional activity as well as many other cellular processes, among the most interesting targets for pharmaceutical research. At present, there is very little information on the structure, specificity, and regulation of various HDACs. This project will focus on structural studies on selected HDACs - to start with HDAC-6, -10, and -11 - and their binding partners. HDAC-6 is a tubulin deacetylase, whereas the biological functions of HDAC-10 and -11 are not very well characterized. In addition to the HDAC catalytic domains, structures of the regulatory domains and binding partners will be pursued. Also inhibitors and substrate-peptides will be used for co-crystallization experiments. Formins are large multi-domain proteins that are involved in the formation of actin filaments by binding to the growing end of actin filaments and e.g. profilins. Diaphanous-related formins are autoregulated, but many other formin family members lack the autoregulatory domains. Many questions remain to be answered concerning the complex regulation of formins and the specificity of different formins with respect to different profilins. Recently, formins have been suggested to affect also microtubule dynamics by co-operating with HDAC-6. The biological significance of this finding remains to be confirmed, but this opens up a new intriguing path to the HDAC and formin field.
Field of science
- /natural sciences/earth and related environmental sciences/geology/mineralogy/crystallography
- /natural sciences/biological sciences/biochemistry/biomolecules/proteins
- /natural sciences/biological sciences/biochemistry
Call for proposal
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