title: Binding of longer Aβ to transmembrane domain 1 of presenilin 1 impacts on Aβ42 generation.
abstract: BACKGROUND
  Amyloid-β peptide ending at 42nd residue (Aβ42) is believed as a pathogenic peptide for Alzheimer disease. Although γ-secretase is a responsible protease to generate Aβ through a processive cleavage, the proteolytic mechanism of γ-secretase at molecular level is poorly understood.
  
  
  RESULTS
  We found that the transmembrane domain (TMD) 1 of presenilin (PS) 1, a catalytic subunit for the γ-secretase, as a key modulatory domain for Aβ42 production. Aβ42-lowering and -raising γ-secretase modulators (GSMs) directly targeted TMD1 of PS1 and affected its structure. A point mutation in TMD1 caused an aberrant secretion of longer Aβ species including Aβ45 that are the precursor of Aβ42. We further found that the helical surface of TMD1 is involved in the binding of Aβ45/48 and that the binding was altered by GSMs as well as TMD1 mutation.
  
  
  CONCLUSIONS
  Binding between PS1 TMD1 and longer Aβ is critical for Aβ42 production.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ohki
authors.forename: Naoaki
authors.initials: N
authors.lastname: Shimada
authors.forename: Aya
authors.initials: A
authors.lastname: Tominaga
authors.forename: Satoko
authors.initials: S
authors.lastname: Osawa
authors.forename: Takuya
authors.initials: T
authors.lastname: Higo
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yokoshima
authors.forename: Tohru
authors.initials: T
authors.lastname: Fukuyama
authors.affiliation: Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. taisuke@mol.f.u-tokyo.ac.jp.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Tomita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000378:metabolism*; D053764:Presenilin-1 / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42)