title: Homodimerization Protects the Amyloid Precursor Protein C99 Fragment from Cleavage by γ-Secretase.
abstract: The amyloid precursor protein (APP) is a single-span integral membrane protein whose C-terminal fragment C99 is cleaved within the transmembrane helix by γ-secretase. Cleavage produces various Aβ peptides that are linked to the etiology of Alzheimer's disease. The transmembrane helix is known to homodimerize in a sequence-specific manner, and considerable controversy about whether the homodimeric form of C99 is cleaved by γ-secretase exists. Here, we generated various covalent C99 homodimers via cross-linking at engineered cysteine residues. None of the homodimers was cleaved in vitro by purified γ-secretase, strongly suggesting that homodimerization protects C99 from cleavage.
authors.affiliation: BMC-Biomedical Center, Metabolic Biochemistry, Ludwig-Maximilians-University , Munich, Germany.
authors.forename: Edith
authors.initials: E
authors.lastname: Winkler
authors.affiliation: Lehrstuhl Chemie der Biopolymere, Technische Universität München , Weihenstephaner Berg 3, 85354 Freising, Germany.|Munich Center For Integrated Protein Science (CIPSM) , Munich, Germany.
authors.forename: Ayse
authors.initials: A
authors.lastname: Julius
authors.affiliation: BMC-Biomedical Center, Metabolic Biochemistry, Ludwig-Maximilians-University , Munich, Germany.|DZNE-German Center for Neurodegenerative Diseases , Munich, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Steiner
authors.affiliation: Lehrstuhl Chemie der Biopolymere, Technische Universität München , Weihenstephaner Berg 3, 85354 Freising, Germany.|Munich Center For Integrated Protein Science (CIPSM) , Munich, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Langosch
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D003545:Cysteine / Q000032:analysis / Q000378:metabolism; D006801:Humans; D055503:Protein Multimerization
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D003545:Cysteine