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

The amyloid precursor protein (APP) is a single-span integral membrane protein whose C-terminal fragment C99 is cleaved within the transmembrane helix by 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 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 secretase, strongly suggesting that homodimerization protects C99 from cleavage.