Dynamic palmitoylation of the sodium-calcium exchanger modulates its structure, affinity for lipid ordered domains, and inhibition by XIP

Gök, C. , Plain, F., Robertson, A., Howie, J., Baillie, G. S. , Fraser, N. J. and Fuller, W. (2020) Dynamic palmitoylation of the sodium-calcium exchanger modulates its structure, affinity for lipid ordered domains, and inhibition by XIP. Cell Reports, 31(10), 107697. (doi: 10.1016/j.celrep.2020.107697) (PMID:32521252) (PMCID:PMC7296346)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Howie, Dr Jacqueline and Fraser, Dr Niall and Fuller, Dr Will and Robertson, Dr Alan and Baillie, Professor George and Gok, Mr Caglar
Creator Roles:
Gök, C.Conceptualization, Methodology, Investigation, Writing – review and editing
Fuller, W.Conceptualization, Writing – original draft, Supervision, Project administration, Funding acquisition
Fraser, N. J.Investigation, Writing – review and editing, Funding acquisition
Robertson, A.Resources
Howie, J.Resources
Baillie, G. S.Resources
Authors: Gök, C., Plain, F., Robertson, A., Howie, J., Baillie, G. S., Fraser, N. J., and Fuller, W.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Cell Reports
Publisher:Elsevier (Cell Press)
ISSN:2211-1247
ISSN (Online):2211-1247
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Cell Reports 31(10):107697
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
303370The role of NCX1 palmitoylation in cardiac functionWilliam FullerBritish Heart Foundation (BHF)SP/16/3/32317CAMS - Cardiovascular Science
303944BHF Centre of ExcellenceRhian TouyzBritish Heart Foundation (BHF)RE/18/6/34217CAMS - Cardiovascular Science