The second PAH domain of Sin3. Structural biology & NMR methodology.

Contains fulltext : 27562.pdf (publisher's version ) (Open Access)Repression is sometimes a necessity. For instance, our genetic information is encoded on our DNA and is identical in all the cells of our body. However, our cells are not all identical. This means that the genetic information has to be expressed selectively. The expression of the genetic information is precisely regulated by large protein complexes. The protein Sin3 is one of the key proteins, as it forms a scaffold for such a complex. The Sin3-complex represses the expression of genes that are not required for a specific cell. Each of these genes is recognized by a specialized protein, a repressor, which subsequently binds to Sin3. Malfunction of this interaction between the repressor and Sin3 has been linked to cancer and developmental diseases. This research is focused on the molecular mechanism of the interaction between Sin3 and the repression using nuclear magnetic resonance (NMR) as the main investigation technique. Sin3 binds through one of its three poly amphipathic helix (PAH) domains to the SID (Sin3 interacting domain) of the repressor. The three-dimensional structure and the dynamics of the second PAH domain and its interaction with a SID was investigated using both existing and as well as newly developed NMR experiments. The results show that the free PAH2 domain is folded and binds to the SID without large structural changes. This implies that the PAH domain is a template, defining the necessary complementary fold of the SID. In the complex, the SID forms a helix which is tightly wedged between two helices of the PAH domain. The new structure of this complex shows that more residues are involved in this interaction than observed previouslyRadboud Universiteit, Physical Chemistry, 20 september 2006Promotor : Hilbers, C.W. Co-promotor : Vuister, G.W.144 p