VAP-mediated membrane-tethering mechanisms implicate ER-PM contact function in pH homeostasis

VAP-mediated membrane-tethering mechanisms implicate ER-PM contact function in pH homeostasis

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Summary: Vesicle-associated membrane protein (VAMP)-associated proteins (VAPs) are highly conserved endoplasmic reticulum (ER)-resident proteins that establish ER contacts with multiple membrane compartments in many eukaryotes.However, VAP-mediated membrane-tethering mechanisms remain ambiguous.Here, focusing on gold ps5 controller skin fission yeast ER-plasma membrane (PM) contact formation, using systematic interactome analyses and quantitative microscopy, we predict a non-VAP-protein direct binding-based ER-PM coupling.We further reveal that VAP-anionic phospholipid interactions may underlie ER-PM association and define the pH-responsive nature of VAP-tethered membrane contacts.

Such conserved interactions with anionic phospholipids are generally defective in amyotrophic lateral sclerosis-associated human kenya tree coral for sale VAPB mutant.Moreover, we identify a conserved FFAT-like motif locating at the autoinhibitory hotspot of the essential PM proton pump Pma1.This modulatory VAP-Pma1 interaction appears crucial for pH homeostasis.We thus propose an ingenious strategy for maintaining intracellular pH by coupling Pma1 modulation with pH-sensory ER-PM contacts via VAP-mediated interactions.