Spatial organization of palmitoyl acyl transferases governs substrate localization and function

Abstract

Protein palmitoylation is a critical posttranslational modification that regulates protein trafficking, localization, stability, sorting and function. In mammals, addition of this lipid modification onto proteins is mediated by a family of 23 palmitoyl acyl transferases (PATs). PATs often palmitoylate substrates in a promiscuous manner, precluding our understanding of how these enzymes achieve specificity for their substrates. Despite generous efforts to identify consensus motifs defining PAT-substrate specificity, it remains to be determined whether additional factors beyond interaction motifs, such as local palmitoylation, participate in PAT-substrate selection. In this review, we emphasize the role of local palmitoylation, in which substrates are palmitoylated and trapped in the same subcellular compartments as their PATs, as a mechanism of enzymesubstrate specificity. We focus here on non-Golgi-localized PATs, as physical proximity to their substrates enables them to engage in local palmitoylation, compared to Golgi PATs, which often direct trafficking of their substrates elsewhere. PAT subcellular localization may be an under-recognized, yet important determinant of PAT-substrate specificity that may work in conjunction or completely independently of interaction motifs. We also discuss some current hypotheses about protein motifs that contribute to localization of non-Golgi-localized PATs, important for the downstream targeting of their substrates.

Regulation of Dynamic Protein S-Acylation

“…For example, S-acylation of anterograde cargo proteins such as vesicular stomatitis virus G (VSVG) protein and transferrin receptors facilitates their transport from the cis- to the trans- Golgi ( Ernst et al, 2018 ). However, several PATs are also found at the plasma membrane and ER, where local acylation cycles regulate protein functions ( Philippe and Jenkins, 2019 ). The extent by which such local acylation affect protein trafficking is a topic that is still currently under investigation.…”

Post-Translational Modification and Subcellular Compartmentalization: Emerging Concepts on the Regulation and Physiopathological Relevance of RhoGTPases

“…These associations might also underpin a coupling between lipid metabolism (to which the ER is exquisitely sensitive) [176] and PTM regulation of Rho GTPases. In addition, some of the palmitoyltransferases are also localized in the ER, which can also be modulated by mechanical stretching [177,178].…”

Insights into the molecular basis of the palmitoylation and depalmitoylation of NCX1

“…The important take-home message here is that substrate recognition by zDHHC-PATs occurs at the ɑ-helix structure within the NCX1 intracellular loop, and NCX1 can be palmitoylated locally in either Golgi or ER which is determined by the nature of palmitoylation complex. The notion of local palmitoylation has been previously hypothesised for several proteins [ 31 ]. We suggest that integral membrane proteins like NCX1 can be palmitoylated in multiple compartments by multiple zDHHC-PATs.…”