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#palmitoylation

2 public questions tagged with this topic.

Lipid Link Protein

Why does palmitoylation enhance membrane association?

Increasing membrane residence time via acylation leverages hydrophobic insertion energy of long chain fatty acid. S-palmitoylation attaches sixteen-carbon saturated palmitate from palmitoyl-CoA donor to cysteine thiol via thioester bond catalyzed by twenty three mammalian Asp-His-His-Cys palmitoyl acyltransferases resident in endoplasmic reticulum, Golgi and plasma membrane, reversible by cytosolic acyl-protein thioesterases APT1, APT2 and ABHD17 family enabling dynamic cycling within minutes to hours responsive to neuronal activity and growth factor signaling. Added acyl chain raises partitioning energy about twelve kilocalories per mol promoting stable insertion into cytosolic leaflet and preferential segregation into cholesterol sphingomyelin enriched ordered domains where signaling effectors concentrate. Examples include PSD-95 requiring di-palmitoylation for postsynaptic density clustering of AMPA receptors, H-Ras needing palmitoylation for Golgi to plasma membrane transport, SNAP25 for SNARE mediated fusion and eNOS for caveolar targeting. Thioester lability to neutral hydroxylamine distinguishes it from stable amides, explaining reversible regulation of membrane association. Repeated cycles of acylation and deacylation enable spatiotemporal control of kinase localization during synaptic plasticity and growth factor responses.

Ref: Linder and Deschenes, Protein Palmitoylation and Membrane Targeting, Nature Reviews Mol Cell Biol 2007.

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Lipid Link Protein

Which of the following lipid modifications involves thioether bond formation?

Lipid modifications differ in chemistry of linkage and reversibility. N-myristoylation forms amide bond between myristate and N-terminal glycine co-translationally irreversible, palmitoylation forms thioester between 16-carbon palmitate and cysteine thiol reversibly cleaved by acyl protein thioesterases, GPI anchoring forms amide between ethanolamine phosphate and C-terminus plus glycosidic linkages to inositol phospholipid. Prenylation, either farnesylation 15-carbon or geranylgeranylation 20-carbon, occurs at C-terminal CAAX motif where X determines farnesyl vs geranylgeranyl transferase specificity. Farnesyltransferase and geranylgeranyltransferase I catalyze attack of cysteine thiolate on isoprenoid pyrophosphate forming thioether bond C-S-C that is stable, irreversible and requires subsequent proteolysis of AAX residues and carboxymethylation for full membrane targeting. Ras, Rho, Rab and nuclear lamins use prenylation for membrane anchoring necessary for signaling, cytoskeletal organization and nuclear envelope assembly. Thioester thioether distinction separates palmitoylation from prenylation chemistry and membrane affinity. Such detailed mechanistic insight is frequently examined in competitive tests including NEET, CUET, CSIR-NET and GATE where transporter classification, energetics and disease linkage are integrated into problem-solving questions.

Ref: Wang & Casey, Nat Rev Mol Cell Biol 2016, Protein prenylation and thioether linkage.

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