title: Participation of transmembrane domain 1 of presenilin 1 in the catalytic pore structure of the γ-secretase.
abstract: γ-Secretase is an intramembrane-cleaving protease that is responsible for the generation of amyloid-β peptides linked to the pathogenesis of Alzheimer's disease. Using a substituted cysteine accessibility method, we have previously shown that the hydrophilic "catalytic pore" structure of γ-secretase is formed by the transmembrane domains (TMDs) 6, 7, and 9 of presenilin 1 (PS1), the catalytic subunit of γ-secretase, within the membrane. Here, we analyzed the structure in and around the first hydrophobic region, the putative TMD1, of PS1, of which the precise function as well as three-dimensional location within γ-secretase remained unknown. We found that TMD1 is located in proximity to the catalytic GxGD and PAL motifs within the C-terminal fragment of PS1, facing directly the catalytic pore. Competition experiments using known γ-secretase inhibitors suggested that the N-terminal region of TMD1 functions as a subsite during proteolytic action of the γ-secretase. Intriguingly, binding of inhibitors affected water accessibility of residues at the membrane border of TMD1, suggesting the possibility of a dynamic motion of TMD1 during the catalytic process. Our results provide mechanistic insights into the functional role of TMD1 of PS1 in the intramembrane-cleaving activity of the γ-secretase.
authors.affiliation: Department of Neuropathology and Neuroscience, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Takagi
authors.forename: Aya
authors.initials: A
authors.lastname: Tominaga
authors.forename: Chihiro
authors.initials: C
authors.lastname: Sato
authors.forename: Taisuke
authors.initials: T
authors.lastname: Tomita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
mesh_terms: D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry* / Q000235:genetics; D000818:Animals; D020134:Catalytic Domain / Q000502:physiology*; D002460:Cell Line; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D053764:Presenilin-1 / Q000737:chemistry* / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000502:physiology
chemical_list: D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases