TY - JOUR T1 - Participation of Transmembrane Domain 1 of Presenilin 1 in the Catalytic Pore Structure of the γ-Secretase JF - The Journal of Neuroscience JO - J. Neurosci. SP - 15943 LP - 15950 DO - 10.1523/JNEUROSCI.3318-10.2010 VL - 30 IS - 47 AU - Shizuka Takagi AU - Aya Tominaga AU - Chihiro Sato AU - Taisuke Tomita AU - Takeshi Iwatsubo Y1 - 2010/11/24 UR - http://www.jneurosci.org/content/30/47/15943.abstract N2 - 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. ER -