title: The histidine composition of the amyloid-β domain, but not the E1 copper binding domain, modulates β-secretase processing of amyloid-β protein precursor in Alzheimer's disease.
abstract: Amyloid-β protein precursor (AβPP) proteolysis by β- and γ-secretases generates neurotoxic amyloid-β (Aβ)-peptides in Alzheimer's disease (AD). We have investigated the role of histidine residues within the extracellular E1 copper binding and Aβ domains of AβPP in its proteolysis. By stably expressing histidine to alanine AβPP mutant constructs in SH-SY5Y cells, we show that mutations in the E1 copper binding domain had no impact on α- or β-secretase processing. Mutation of histidine 14 within the Aβ-domain specifically down-regulated β-secretase processing without impacting on non-amyloidogenic proteolysis. Understanding how histidine 14 participates in AβPP proteolysis may reveal new intervention points for AD treatments.
authors.affiliation: Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, UK.
authors.forename: Mallory
authors.initials: M
authors.lastname: Gough
authors.affiliation: Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, UK.
authors.forename: Sophee
authors.initials: S
authors.lastname: Blanthorn-Hazell
authors.affiliation: Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, UK.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Parkin
mesh_terms: D000409:Alanine; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003300:Copper / Q000378:metabolism; D057809:HEK293 Cells; D006639:Histidine; D006801:Humans; D009154:Mutation; D017434:Protein Structure, Tertiary; D014162:Transfection
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D006639:Histidine; D003300:Copper; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine
keywords: Amyloid-β protein precursor; amyloidogenic processing; histidine 14; β-secretase