Topical review: shedding light on molecular and cellular consequences of NCX1 palmitoylation

Gök, C. and Fuller, W. (2020) Topical review: shedding light on molecular and cellular consequences of NCX1 palmitoylation. Cellular Signalling, 76, 109791. (doi: 10.1016/j.cellsig.2020.109791) (PMID:32980495)

Abstract

Palmitoylation is the post-translational, covalent and reversible conjugation of a 16C saturated fatty acid to cysteine residues of proteins. The sodium calcium exchanger NCX1 is palmitoylated at a single cysteine residue in its large regulatory intracellular loop. Inactivation, mediated by the NCX1 inhibitory region XIP, is drastically impaired in unpalmitoylatable NCX1. The ability of XIP to bind and inactivate NCX1 is largely determined by NCX1 palmitoylation, which induces local conformational changes in the NCX1 intracellular loop to enable XIP to engage its binding site. Consequently, NCX1 palmitoylation regulates intracellular calcium by changing NCX1 sensitivity to inactivation. NCX1 palmitoylation is a dynamic phenomenon which is catalyzed by the palmitoyl acyl transferase zDHHC5 and reversed by the thioesterase APT1, with the switch between palmitoylated and depalmitoylated states, which has profound effects on NCX1 lipid interactions, influenced by NCX1 conformational poise. Herein we review the molecular and cellular consequences of NCX1 palmitoylation and its physiological relevance and highlight the importance of palmitoylation for NCX1 activity. We discuss the cellular control of protein palmitoylation and depalmitoylation, the relationship between lipid microdomains and lipidated and phospholipid binding proteins, and highlight the important unanswered questions in this emerging field.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Fuller, Professor Will and Gok, Dr Caglar
• Authors: Gök, C., and Fuller, W.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Cellular Signalling
• Publisher: Elsevier
• ISSN: 0898-6568
• ISSN (Online): 1873-3913
• Published Online: 24 September 2020
• Copyright Holders: Copyright © 2020 Elsevier Inc.
• First Published: First published in Cellular Signalling 76:109791
• Publisher Policy: Reproduced in accordance with the publisher copyright policy

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
303370		The role of NCX1 palmitoylation in cardiac function	William Fuller	British Heart Foundation (BHF)	SP/16/3/32317	CAMS - Cardiovascular Science