1.A.121.  The Anterior Pharynx-defective Water Channel (APH-WC) Family 

The four-subunit protease complex, gamma-secretase (TC# 4.G.1), cleaves many single-pass transmembrane (TM) substrates, including Notch and beta-amyloid precursor protein to generate amyloid-beta (Abeta), central to Alzheimer's disease. Two of the subunits, anterior pharynx-defective 1 (APH-1) and presenilin (PS) exist in two homologous forms APH1-A and APH1-B, and PS1 and PS2, respectively. Dehury and Kepp 2020 developed a complete structural model of the APH-1B subunit using the published cryo-EM structures of APH1-A (PDB: 5FN2, 5A63, and 6IYC). All-atom molecular dynamics simulations at 303 K in a realistic bilayer system revealed how APH-1B alone and in gamma-secretase without and with substrate C83-bound adopts a 7 TMS topology with a water channel topology similar to APH-1A. They demonstrated direct transport of water through this channel, mainly via Glu84, Arg87, His170, and His196. The apo and holo states closely resemble the experimental cryo-EM structures with APH-1A, but with subtle differences: The substrate-bound APH-1B gamma-secretase was quite stable, but some TM helices of PS1 and APH-1B rearranged in the membrane consistent with the disorder seen in the cryo-EM data. This produces different accessibility of water molecules for the catalytic aspartates of PS1, critical for Abeta production. In particular, the typical distance between the catalytic aspartates of PS1 and the C83 cleavage sites are shorter in APH-1B; that is, it represents a more closed state, due to interactions with the C-terminal fragment of PS1. The structural-dynamic model of APH-1B alone and in gamma-secretase suggests generally similar topologies with some notable differences in water accessibility, which may be relevant to the protein's existence in two forms and their specific function and location (Dehury and Kepp 2020).

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