Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.01.12.523872v1?rss=1

Authors: Hoh, K. L., Mu, B., See, T., Ng, A. Y. E., Ng, A. Q. E., Zhang, D.

Abstract:
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 fission yeast ER-plasma membrane (PM) contact formation, using systematic interactome analyses and quantitative microscopy, we predict a non-protein-protein binding-based tethering mechanism of VAPs. We further demonstrate that VAP-anionic phospholipids interactions underlie ER-PM association and define the pH-responsive nature of VAP-tethered membrane contacts. Importantly, such conserved interactions, particularly with phosphatidylinositol 4-phosphate (PI4P) and phosphatidylinositol (PI), are defective in amyotrophic lateral sclerosis (ALS)-associated human 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 is crucial for pH homeostasis. We thus propose an ingenious strategy for maintaining intracellular pH by coupling Pma1 modulation with pH-biosensory ER-PM contacts via VAP-mediated interactions.

Copy rights belong to original authors. Visit the link for more info

Podcast created by Paper Player, LLC