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

TY - JOUR

T1 - Control of protein palmitoylation by regulating substrate recruitment to a zDHHC-protein acyltransferase

AU - Plain, Fiona

AU - Howie, Jacqueline

AU - Kennedy, Jennifer

AU - Brown, Elaine

AU - Shattock, Michael J.

AU - Fraser, Niall J.

AU - Fuller, William

N1 - This work was supported by grants from the British Heart Foundation (FS/14/68/30988 to W.F. and N.F., RG/17/15/33106 to W.F., N.F. and M.J.S.).

PY - 2020/7/31

Y1 - 2020/7/31

N2 - 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.

AB - 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.

KW - Cell signalling

KW - Post-translational modifications

UR - https://www.scopus.com/pages/publications/85088875548

U2 - 10.1038/s42003-020-01145-3

DO - 10.1038/s42003-020-01145-3

M3 - Article

C2 - 32737405

SN - 2399-3642

VL - 3

JO - Communications Biology

JF - Communications Biology

IS - 1

M1 - 411

ER -