Dynamic Palmitoylation of the Sodium-Calcium Exchanger Modulates Its Structure, Affinity for Lipid-Ordered Domains, and Inhibition by XIP.

Cell Reports
Caglar GökWilliam Fuller

Abstract

The transmembrane sodium-calcium (Na-Ca) exchanger 1 (NCX1) regulates cytoplasmic Ca levels by facilitating electrogenic exchange of Ca for Na. Palmitoylation, the only reversible post-translational modification known to modulate NCX1 activity, controls NCX1 inactivation. Here, we show that palmitoylation of NCX1 modifies the structural arrangement of the NCX1 dimer and controls its affinity for lipid-ordered membrane domains. NCX1 palmitoylation occurs dynamically at the cell surface under the control of the enzymes zDHHC5 and APT1. We identify the position of the endogenous exchange inhibitory peptide (XIP) binding site within the NCX1 regulatory intracellular loop and demonstrate that palmitoylation controls the ability of XIP to bind this site. We also show that changes in NCX1 palmitoylation change cytosolic Ca. Our results thus demonstrate the broad molecular consequences of NCX1 palmitoylation and highlight a means to manipulate the inactivation of this ubiquitous ion transporter that could ameliorate pathologies linked to Ca overload via NCX1.

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Citations

Jan 13, 2021·Molecular Brain·Benjun Ji, Małgorzata Skup
Apr 2, 2021·Science Advances·Amandine VirlogeuxFrédéric Saudou
Apr 1, 2021·Open Biology·Luke H ChamberlainGwyn W Gould
Sep 28, 2020·Cellular Signalling·Caglar Gök, William Fuller
May 14, 2021·Frontiers in Molecular Biosciences·Jessica J ChenDarren Boehning
Jun 25, 2021·Frontiers in Pharmacology·Pimthanya WanichawanCathrine Rein Carlson
Nov 6, 2021·Biology of the Cell·Maxime Jansen, Bruno Beaumelle

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Methods Mentioned

BETA
FRET
Affinity
Peptide array
pull
affinity-purification
transfection
confocal microscopy
affinity purification

Software Mentioned

Fiji
MetaFluor
GraphPad Prism

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