Fluhrer, Regina; Kamp, Frits; Grammer, Gudula; Nuscher, Brigitte; Steiner, Harald; Beyer, Klaus; Haass, Christian
The Nicastrin ectodomain adopts a highly thermostable structure.
In: Biological Chemistry, Vol. 392, Nr. 11: S. 995-1001
Nicastrin is a type I transmembrane glycoprotein, which is part of the high molecular weight gamma-secretase complex. gamma-Secretase is one of the key players associated with the generation of Alzheimer's disease pathology, since it liberates the neurotoxic amyloid beta-peptide. Four proteins Nicastrin, anterior pharynx-defective-1 (Aph-1), presenilin enhancer-2 (Pen-2) and Presenilin are essential to form the active gamma-secretase complex. Recently it has been shown, that Nicastrin has a key function in stabilizing the mature gamma-secretase complex and may also be involved in substrate recognition. So far no structural data for the Nicastrin ectodomain or any other gamma-secretase component are available. We therefore used Circular Dichroism (CD) spectroscopy to demonstrate that Nicastrin, similar to its homologues, the Streptomyces griseus aminopeptidase (SGAP) and the transferrin receptor (TfR), adopts a thermostable secondary structure. Furthermore, the Nicastrin ectodomain has an exceptionally high propensity to refold after thermal denaturation. These findings provide evidence to further support the hypothesis that Nicastrin may share evolutionary conserved properties with the aminopeptidase and the transferrin receptor family.