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Article type: Research Article
Authors: Mao, Guozhanga | Tan, Jianxina | Cui, Mei-Zhena | Chui, Dehuab | Xu, Xuemina; *
Affiliations: [a] Department of Pathobiology College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA | [b] Peking University Health Science Center, Hai Dian District, Beijing, China
Correspondence: [*] Corresponding author: Xuemin Xu, PhD, Department of Pathobiology, College of Veterinary Medicine, The University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA. Tel.: +1 865 974 8206; Fax: +1 865 974 5616; E-mail: xmx@utk.edu.
Abstract: γ-secretase-mediated processing of the amyloid-β protein precursor (AβPP) is a crucial step in the formation of the amyloid-β peptide (Aβ), but little is known about how the substrate AβPP interacts with the γ-secretase complex. To understand the molecular events involved in γ-secretase-mediated AβPP processing and Aβ formation, in the present study we determined the role of a well conserved GxxxG motif in the transmembrane domain of AβPP. Our data clearly demonstrate that substitution of aspartic acid for the key glycine residues in the GxxxG motif almost completely abolished the formation of Aβ. Furthermore, our data revealed that substitution of aspartic acid for the glycine in this GxxxG motif disrupts the interaction of AβPP with the γ-secretase complex. Thus, the present study revealed an essential role for the GxxxG motif in the interaction of AβPP with the γ-secretase complex and the formation of Aβ.
Keywords: Alzheimer's disease, amyloid-β peptide, amyloid-β precursor protein, GxxxG motif, γ-secretase
DOI: 10.3233/JAD-2009-1132
Journal: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 167-176, 2009
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