Research Team - Dr. Dieter Maier

Structure, function and evolution of Hairless and other Notch-pathway components

Hairless (H) is a major antagonist of the Notch signaling pathway in Drosophila (1). H protein binds to Su(H), thereby repressing the activation of Notch target genes. The H gene encodes a highly basic pioneer protein and is ubiquitously expressed during development. Two H protein isoforms of different size are observed (~120 kDa, ~150 kDa). The Hp150 isoform corresponds to the full length protein conventionally translated in a Cap-dependent manner, whereas Hp120 is translated from an internal ribosome entry site also during mitosis (2). Surprisingly, both isoforms show only slightly different activity in vivo. Despite a striking conservation of the Notch signalling pathway from worm and fly to human (3), H has not been found outside of insects. By looking at the very distant species Apis mellifera (honeybee), we find a high conservation within protein domains that serve as binding sites for respective Drosophila partners in vivo. Despite a high degree of variation most remarkably in size, A.m.H can largely replace D.m.H (4).

The antagonistic activity of H involves the formation of a repressor complex formed on Notch target gene promoters. Upon binding of Su(H), H recruits the corepressors Groucho and CtBP resulting in chromatin silencing (5). The switch between activator- and repressor complex is little understood. In a detailed structure-function analysis of the repressor complex we could define the sites of Su(H) contact in H (6). Moreover, we found a competition between H and Notch for binding of Su(H) in vitro (6) as well as in vivo (7). Based on the structure of the Su(H)-H repressor complex (8), Notch and H contact Su(H) at different position, indicating that competition does not occur by expulsion. Rather the large conformational change of Su(H), i.e. allostery of Su(H) is a likely explanation for the switch between activator and repressor complex formation (and vice versa).

selected publications:

1. Maier, D. (2006). Hairless, the ignored antagonist of the Notch signaling pathway. Hereditas 143: 212-221.
2. Maier, D., Nagel, A.C. and Preiss, A. (2002). An IRES within the Notch antagonist Hairless directs protein expression during mitosis. Proc. Natl. Acad. Sci USA 99, 15480-15485.
3. Schlatter, R. and Maier, D. (2005). The Enhancer of split and Achaete-Scute complexes in Drosophilids are derived from simple ur-complexes preserved in mosquito and honeybee. BMC Evolutionary Biology, 5:67, 1-20.
4. Maier, D., Chen A.X., Preiss, A. & Ketelhut, M. (2008). The tiny Hairless protein from  Apis mellifera: a potent antagonist of Notch signaling in Drosophila melanogaster. BMC Evolutionary Biology 8:175, 1-15.
5. Nagel, A.C., Krejci, A.,Tenin, G., Bravo-Patiño, A., Bray, S., Maier, D. and Preiss, A. (2005). Hairless mediated repression of Notch target genes requires co-operation between Groucho and CtBP co-repressors. Mol. Cell Biol. 25 (23), 10433-10441. Mol Biol Cell 21, 3443-344.
6. Maier D., Kurth P., Schulz A., Russell A., Yuan Z., Gruber K., Kovall R.A. & Preiss A. (2011). Structural and functional analysis of the repressor complex in the Notch signaling pathway of D. melanogaster. Mol Biol Cell 22: 3242-3252
7. Maier D., Praxenthaler H., Schulz A., Preiss A. (2013). Gain of function Notch phenotypes associated with ectopic expression of the Su(H) C-terminal domain illustrate separability of Notch- and Hairless-mediated activities. PLoS One 8 (11), e8157.
8. Yuan Z., Praxenthaler H., Tabaja N, Torell R, Preiss A., Maier D. & Kovall R.A. (2016). Structure and function of the Su(H)-Hairless complex, the major anagonist of Notch signaling in Drosophila melanogaster. in preparation