Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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Homodimerization Protects the Amyloid Precursor Protein C99 Fragment from Cleavage by γ-Secretase

Biochemistry. 2015 Oct 13;54(40):6149-52.

Authors/Editors: Winkler E
Julius A
Steiner H
Langosch D
Type of Publication: Journal Article

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.

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