title: The Nicastrin ectodomain adopts a highly thermostable structure.
abstract: Nicastrin is a type I transmembrane glycoprotein, which is part of the high molecular weight γ-secretase complex. γ-Secretase is one of the key players associated with the generation of Alzheimer's disease pathology, since it liberates the neurotoxic amyloid β-peptide. Four proteins Nicastrin, anterior pharynx-defective-1 (Aph-1), presenilin enhancer-2 (Pen-2) and Presenilin are essential to form the active γ-secretase complex. Recently it has been shown, that Nicastrin has a key function in stabilizing the mature γ-secretase complex and may also be involved in substrate recognition. So far no structural data for the Nicastrin ectodomain or any other γ-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.
authors.affiliation: Adolf-Butenandt-Institute, Biochemistry, Ludwig Maximilians University, Schillerstrasse 44, 80336 Munich, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Fluhrer
authors.forename: Frits
authors.initials: F
authors.lastname: Kamp
authors.forename: Gudula
authors.initials: G
authors.lastname: Grammer
authors.forename: Brigitte
authors.initials: B
authors.lastname: Nuscher
authors.forename: Harald
authors.initials: H
authors.lastname: Steiner
authors.forename: Klaus
authors.initials: K
authors.lastname: Beyer
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000626:Aminopeptidases / Q000737:chemistry; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry*; D002460:Cell Line; D002942:Circular Dichroism; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry*; D058849:Protein Refolding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011990:Receptors, Transferrin / Q000737:chemistry; D013305:Streptomyces griseus / Q000201:enzymology; D013696:Temperature
chemical_list: D008562:Membrane Glycoproteins; D011990:Receptors, Transferrin; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases; D000626:Aminopeptidases