Conformational variability of the intracellular domain of Drosophila Notch and its interaction with Suppressor of Hairless
- *Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115;
- †Massachusetts General Hospital Cancer Center, 149 13th Street, Charlestown, MA 02129; and
- ‡Collège de France, 75231 Paris, France
-
Communicated by Vincent T. Marchesi, Yale University School of Medicine, New Haven, CT, April 9, 2007 (received for review December 28, 2006)
Abstract
The Notch receptor is the central element in an evolutionarily conserved signal transduction pathway that controls cell fates in metazoans. Receptor–ligand interactions trigger a cascade of proteolytic events that release the entire Notch intracellular domain (NICD) from the membrane, permitting its translocation into the nucleus and participation in a transcriptionally active complex. Using electron microscopy, we examined the structure of NICD and its interaction with the DNA-binding effector of Notch signaling, Suppressor of Hairless [Su(H)]. In conjunction with biochemical analyses, we found that Drosophila NICD is monomeric and exists in two primary conformational states, only one of which can bind Su(H). Furthermore, we show that changes in divalent cation concentrations lead to NICD self-association, which seems to be mediated by the polyglutamine-containing, opa-repeat region of NICD. Our study suggests that conformational modulation of NICD may define a mechanism of Notch pathway control.
Footnotes
- §To whom correspondence should be addressed. E-mail: tsakonas{at}helix.mgh.harvard.edu
-
Author contributions: D.F.K. and R.J.L. contributed equally to this work; D.F.K., R.J.L., T.W., and S.A.-T. designed research; D.F.K. and R.J.L. performed research; R.J.L. and S.A.-T. contributed new reagents/analytic tools; D.F.K., R.J.L., T.W., and S.A.-T. analyzed data; and D.F.K., R.J.L., T.W., and S.A.-T. wrote the paper.
-
The authors declare no conflict of interest.
- Abbreviations:
- NICD,
- Notch intracellular domain;
- Su(H),
- Suppressor of Hairless.
- © 2007 by The National Academy of Sciences of the USA
