Control of protein palmitoylation by regulating substrate recruitment to a zDHHC-protein acyltransferase

Plain, F., Howie, J., Kennedy, J., Brown, E., Shattock, M. J., Fraser, N. J. and Fuller, W. (2020) Control of protein palmitoylation by regulating substrate recruitment to a zDHHC-protein acyltransferase. Communications Biology, 3, 411. (doi: 10.1038/s42003-020-01145-3) (PMID:32737405) (PMCID:PMC7395175)

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Abstract

Although palmitoylation regulates numerous cellular processes, as yet efforts to manipulate this post-translational modification for therapeutic gain have proved unsuccessful. The Na-pump accessory sub-unit phospholemman (PLM) is palmitoylated by zDHHC5. Here, we show that PLM palmitoylation is facilitated by recruitment of the Na-pump α sub-unit to a specific site on zDHHC5 that contains a juxtamembrane amphipathic helix. Site-specific palmitoylation and GlcNAcylation of this helix increased binding between the Na-pump and zDHHC5, promoting PLM palmitoylation. In contrast, disruption of the zDHHC5-Na-pump interaction with a cell penetrating peptide reduced PLM palmitoylation. Our results suggest that by manipulating the recruitment of specific substrates to particular zDHHC-palmitoyl acyl transferases, the palmitoylation status of individual proteins can be selectively altered, thus opening the door to the development of molecular modulators of protein palmitoylation for the treatment of disease.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Howie, Dr Jacqueline and Fuller, Professor Will and Brown, Miss Elaine
Authors: Plain, F., Howie, J., Kennedy, J., Brown, E., Shattock, M. J., Fraser, N. J., and Fuller, W.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Communications Biology
Publisher:Nature Research
ISSN:2399-3642
ISSN (Online):2399-3642
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Communications Biology 3:411
Publisher Policy:Reproduced under a Creative Commons licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
301690The Na/K ATPase in cardiovascular health and diseaseWilliam FullerBritish Heart Foundation (BHF)RE12627 - RG/17/15/33106CAMS - Cardiovascular Science