MapPIng PI inside cells brings new light to polyphosphoinositide biology

Drin, Guillaume

doi:10.1083/jcb.202001185

Cited by 4 publications

(2 citation statements)

References 10 publications

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“…Moreover, in crude membrane fractions from liver, brain and yeast, the latter was clearly the most thermostabilizing and is the only crude lipid fraction with a high PI content. Interestingly, PI lipids are highly enriched in intracellular organelles 48 , which is the preferential localization of NHA2. However, given that NHA2 can also localize to the plasma membrane of specialized cells 8 , it is currently unclear whether PIP 2 can play a similar role to PI in these membranes.…”

Section: Discussionmentioning

confidence: 99%

Structure, mechanism and lipid-mediated remodeling of the mammalian Na+/H+ exchanger NHA2

Matsuoka

Fudim

Jung

et al. 2022

Nat Struct Mol Biol

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The Na+/H+ exchanger SLC9B2, also known as NHA2, correlates with the long-sought-after Na+/Li+ exchanger linked to the pathogenesis of diabetes mellitus and essential hypertension in humans. Despite the functional importance of NHA2, structural information and the molecular basis for its ion-exchange mechanism have been lacking. Here we report the cryo-EM structures of bison NHA2 in detergent and in nanodiscs, at 3.0 and 3.5 Å resolution, respectively. The bison NHA2 structure, together with solid-state membrane-based electrophysiology, establishes the molecular basis for electroneutral ion exchange. NHA2 consists of 14 transmembrane (TM) segments, rather than the 13 TMs previously observed in mammalian Na+/H+ exchangers (NHEs) and related bacterial antiporters. The additional N-terminal helix in NHA2 forms a unique homodimer interface with a large intracellular gap between the protomers, which closes in the presence of phosphoinositol lipids. We propose that the additional N-terminal helix has evolved as a lipid-mediated remodeling switch for the regulation of NHA2 activity.

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Section: Discussionmentioning

confidence: 99%

Structure, mechanism and lipid-mediated remodeling of the mammalian Na+/H+ exchanger NHA2

Matsuoka

Fudim

Jung

et al. 2022

Nat Struct Mol Biol

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“…Conceivably, major anionic PLs of the PM (comprised of ~ 20% PI, 10% PS and 1% PI 4 P + PI 4,5 P 2 in yeast 31,45 ) are in much higher abundance than VAPs, which makes the extent of ER-PM contacts dependent on VAP dosage. We believe that such tethering mechanism should not be merely limited to S. pombe or to ER-PM contacts, as binding of PI and PI 4 P appears to be conserved in VAP family and other organelles may also contain adequate levels of PI and/or PI 4 P in cytosolic leaflets 30,46 . Thus, much lower PI content in the mammalian PM as compared to that of yeasts 30,47,48 and non-conserved PS-binding ability of VAPs may partially explain different scales of ER-PM association in these cell types.…”

Section: Discussionmentioning

confidence: 99%

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

Hoh

See

et al. 2023

Preprint

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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.

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

Hoh,

Mu,

See

et al. 2024

Cell Reports

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MapPIng PI inside cells brings new light to polyphosphoinositide biology

Cited by 4 publications

References 10 publications

Structure, mechanism and lipid-mediated remodeling of the mammalian Na+/H+ exchanger NHA2

Structure, mechanism and lipid-mediated remodeling of the mammalian Na+/H+ exchanger NHA2

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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