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Biochemistry. 2015 Oct 13;54(40):6149-52. doi: 10.1021/acs.biochem.5b00986. Epub 2015 Sep 29.

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

Author information

1
BMC-Biomedical Center, Metabolic Biochemistry, Ludwig-Maximilians-University , Munich, Germany.
2
Lehrstuhl Chemie der Biopolymere, Technische Universität München , Weihenstephaner Berg 3, 85354 Freising, Germany.
3
Munich Center For Integrated Protein Science (CIPSM) , Munich, Germany.
4
DZNE-German Center for Neurodegenerative Diseases , Munich, Germany.

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.

PMID:
26403946
DOI:
10.1021/acs.biochem.5b00986
[Indexed for MEDLINE]

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