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).
Anterior pharynx-defective 2 (APH-1B) water channel protein of 257 aas and 7 TMSs in a 3 + 1 + 3 TMS arrangement (Dehury and Kepp 2020).
APH-1B of Homo sapiens
Uncharacterized protein of 282 aas and 7 TMSs in a 3 + 2 + 2 TMS arrangement.
UP of Allomyces macrogynus
Anterior pharynx-defective 1A (APH-1A) of 265 aas and 7 TMSs in a 3 + 4 TMS arrangement (Dehury and Kepp 2020). See family description for details.
APH-1A of Homo sapiens
Gamma-secretase subunit APH1-like of208 aas and 7 TMSs in a 3 + 2 + 2 TMS arrangement.
APH1 of Olea europaea subsp. europaea
Uncharacterized protein of 260 aas and 7 TMSs in a 3 + 4 TMS arrangement.
UP of Cannabis sativa
Uncharacterized protein of 932 aas with a APH domain at the N-terminus with 7 TMSs, a large central hydrophilic domain (or domains) and a C-terminal PE-PGRS domain (TC# 9.B.96).
UP of Gonium pectorale
Uncharacterized protein of 259 aas and 7 TMSs in a 3 + 4 TMS arrangement.
UP of Aphanomyces astaci
APH1 of 275 aas and 7 TMSs
APH1 of Chlorella sorokiniana
Uncharacterized protein of 745 aas with a strongly hydrophilic ~500 aas followed by 7 C-terminal TMSs (the APH domain).
UP of Nothophytophtyora sp. Chile5
Uncharacterized protein of 348 aas with 3 N-terminal TMSs, followed by a hydrophilc region of ~100 aas, followed by 4 TMSs.
UP of Polysphondylium violaceum