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

Fiona Plain, Jacqueline Howie, Jennifer Kennedy, Elaine Brown, Michael J Shattock, Niall J Fraser, William Fuller

Communications biology 2020 Jul 31

filter terms:

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.

Citation

Fiona Plain, Jacqueline Howie, Jennifer Kennedy, Elaine Brown, Michael J Shattock, Niall J Fraser, William Fuller. Control of protein palmitoylation by regulating substrate recruitment to a zDHHC-protein acyltransferase. Communications biology. 2020 Jul 31;3(1):411