Abstract
S-palmitoylation (S-PALM) is a lipid modification that involves the linkage of a fatty acid chain to cysteine residues of the substrate protein. This common posttranslational modification (PTM) is unique among other lipid modifications because of its reversibility. Hence, like phosphorylation or ubiquitination, it can act as a switch that modulates various important physiological pathways within the cell. Numerous studies revealed that S-PALM plays a crucial role in protein trafficking and function throughout the nervous system. Notably, the dynamic turnover of palmitate on proteins at the synapse may provide a key mechanism for rapidly changing synaptic strength. Indeed, palmitate cycling on postsynaptic density-95 (PSD-95), the major postsynaptic density protein at excitatory synapses, regulates the number of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and thus affects synaptic transmission. Accumulating evidence suggests a relationship between impairments in S-PALM and severe neurological disorders. Therefore, determining the precise levels of S-PALM may be essential for understanding the ways in which this PTM is regulated in the brain and controls synaptic dynamics. Protein S-PALM can be characterized using metabolic labeling methods and biochemical tools. Both approaches are discussed herein in the context of specific methods and their advantages and disadvantages. This review clearly shows progress in the field, which has led to the development of new, more sensitive techniques that enable the detection of palmitoylated proteins and allow predictions of potential palmitate binding sites. Unfortunately, one significant limitation of these approaches continues to be the inability to use them in living cells.
Highlights
Protein S-acylation is a lipid modification that involves the covalent attachment of long-chain fatty acids to thiol groups of cysteine (Cys) residues through thioester linkage
Twenty-three distinct DHHC among protein acyltransferases (PATs) have been identified in mammalian cells, which mediate the bulk of protein palmitoylation (Noritake et al, 2009; Ohno et al, 2012)
The purpose of this review is to demonstrate that the S-PALM-based regulation of synaptic proteins is not accidental, but highly defined to specific molecules and pathways that can be modified in neurological disorders
Summary
Protein S-acylation is a lipid modification that involves the covalent attachment of long-chain fatty acids to thiol groups of cysteine (Cys) residues through thioester linkage. Of particular interest is the γ2 subunit, which is required for targeting GABAARs to inhibitory synapses (Luscher et al, 2011) This subunit is S-palmitoylated on multiple cysteine residues in the cytoplasmic region, and this mechanism regulates the normal expression of GABAARs at the cell surface of neurons (Vithlani et al, 2011) (Figure 3A). Immunofluorescent analyses of neurons transfected with a GODZ-specific shRNA vectors revealed a marked reduction of punctate γ2 subunit immunoreactivity as well as loss of postsynaptic gephyrin staining compared with neurons transfected with control shRNA (Fang et al, 2006) From these studies it is evident that the S-PALM of GABAARs is implicated in the dynamic regulation of membrane localization and function of these receptors, thereby modulating GABAergic inhibitory transmission. The effect of 5-HT receptor S-PALM on structural plasticity that underlies depression remains to be elucidated
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