Abstract
S-Acylation, the reversible post-translational lipid modification of proteins, is an important mechanism to control the properties and function of ion channels and other polytopic transmembrane proteins. However, although increasing evidence reveals the role of diverse acyl protein transferases (zDHHC) in controlling ion channel S-acylation, the acyl protein thioesterases that control ion channel deacylation are very poorly defined. Here we show that ABHD17a (α/β-hydrolase domain-containing protein 17a) deacylates the stress-regulated exon domain of large conductance voltage- and calcium-activated potassium (BK) channels inhibiting channel activity independently of effects on channel surface expression. Importantly, ABHD17a deacylates BK channels in a site-specific manner because it has no effect on the S-acylated S0–S1 domain conserved in all BK channels that controls membrane trafficking and is deacylated by the acyl protein thioesterase Lypla1. Thus, distinct S-acylated domains in the same polytopic transmembrane protein can be regulated by different acyl protein thioesterases revealing mechanisms for generating both specificity and diversity for these important enzymes to control the properties and functions of ion channels.
Highlights
Protein S-acylation, the dynamic and reversible postranslational modification of cysteines residues through addition of a fatty acid via a labile thioester bond, is an important modulator of the lifecycle of many polytopic transmembrane proteins including receptors, transporters and ion channels [1,2,3,4]
We have previously revealed that the trafficking, function and regulation of pore forming subunit (Kcnma1) of the large conductance calcium- and voltage activated potassium (BK) channel is controlled by S-acylation of two distinct domains (Figure 1A)
We demonstrate that a/b-hydrolase domain-containing protein 17a (ABHD17a) is an acyl protein thioesterase that deacylates the stress regulated exon (STREX), but not S0-S1, domain of BK channels and in accordance with its specificity for the STREX domain controls channel activity rather than channel trafficking
Summary
Protein S-acylation, the dynamic and reversible postranslational modification of cysteines residues through addition of a fatty acid (typically the 16-carbon fatty acid palmitate) via a labile thioester bond, is an important modulator of the lifecycle of many polytopic transmembrane proteins including receptors, transporters and ion channels [1,2,3,4]. The intracellular loop between transmembrane domains S0 and S1 (S0-S1 loop) is S-acylated at a cluster of conserved cysteine residues that controls trafficking to the plasma membrane and functional assembly with regulatory b1-accessory subunits [15, 16]. This domain is largely S-acylated by zDHHC23 that promotes membrane trafficking of the a-subunit alone and is a target for deacylation by Lypla resulting in channel retention in the trans Golgi network [15]. We demonstrate that ABHD17a is an acyl protein thioesterase that deacylates the STREX, but not S0-S1, domain of BK channels and in accordance with its specificity for the STREX domain controls channel activity rather than channel trafficking
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