Protein-function and -variety is regulated by processes as alternative splicing and post-translational modification. Dysfunction in these processes can lead to severe diseases within the human body. Post-translational modification as phosphorylation and ubiquitylation has been extensively studied for many years. In contrast, acetylation of the epsilon amine of specific lysine residues has seen little investigation so far.

Lysine-acetylation seems to be a reversible post-translational modification with many diverse roles and a functional importance that even rivals phosphorylation. The processes of acetylation and deacetylation are highly dynamic and regulated by acetyl-CoA dependent histone/lysine acetyl-transferases (KATs), removed by Zn-dependent histone/lysine deacetylases (HDACs/KDACs) or NAD-dependent sirtuins. For histones and transcription factors it could be shown that the acetylation state plays an important role for the coordination of gene-expression and cell-cycle progression.

Recent mass spectrometry and immunofluorescence studies have demonstrated that thousands of non-histone proteins are acetylated in mammalian cells in all cellular compartments. Many of the proteins identified are important for regulation of the cytoskeleton (RhoGTPase-exchange factors, Rho-guanine nucleotide dissociation inhibitors, GTPase-activating proteins, formins, tubulin, profilin, actin, etc.). This shows that acetylation may form a highly important regulative mechanism controlling cytoskeleton function. This has only been marginally investigated so far.

The cytoskeleton has been in centre of scientific interest for several years. It contains hundreds of accessory proteins and is essential for the major events in a living cell: apoptosis, cell shape, transport processes, cell migration, wound healing, replication, cell differentiation and cell signaling. The complexity of the cytoskeleton is immense and, therefore, cytoskeleton research is still of highest importance. Deregulation and aberrations in cytoskeletal-proteins lead to several severe diseases in the human body comprising muscle- and neurodegenerative diseases, cancer and cardiovascular diseases.

We are particularly interested in the following questions:

• How does acetylation control protein function and affect cellular regulation?

• How is acetylation regulated in human cells?

• How does the cellular acetylation pattern of cytoskeletal proteins change depending on the physiological state or treatment with different stimuli?

• How is the impact of acetylation for cytoskeleton function and what are consequences of its dysfunction (i.e. metastasis, invasion)?

To test our hypothesis concerning the functional role of lysine-acetylation for cytoskeletal function we will apply a broad range of methods including cell biological, biochemical and biophysical techniques including X-ray crystallography. We will use the genetic-code-expansion concept to study the effect of lysine-acetylation on the regulation of the cytoskeleton. This will support basic research in understanding general principles and mechanisms by which acetylation controls cytoskeletal function and will furthermore provide important support for medical applications. Several drugs that affect activities of cytoskeletal proteins are under intensive pharmaceutical investigation, some are already in use. Furthermore, it will support the design of more specific KDAC inhibitors as anti-cancer drugs with less off-target effects.

For further information please read listed literature.