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.
Highlights
Palmitoylation regulates numerous cellular processes, as yet efforts to manipulate this post-translational modification for therapeutic gain have proved unsuccessful
We have shown by truncation analysis that a region on zDHHC5 located between N218 and T334 is required for Na-pump binding and PLM palmitoylation[13]
The zDHHC20 palmitoyltransferase conserved C-terminus (PaCCT) motif contains an amphipathic helix[35] which is conserved in zDHHC5 (Fig. 1c)
Summary
Palmitoylation regulates numerous cellular processes, as yet efforts to manipulate this post-translational modification for therapeutic gain have proved unsuccessful. 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. ZDHHC-PATs are characterized by a cysteine-rich region with a conserved Asp-HisHis-Cys (DHHC) motif[17] within the active site[18]; there are 23 human isoforms. The palmitoylation status of specific proteins may be changed by selectively manipulating their recruitment to (a) cognate zDHHC-PAT(s)
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