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#myristoylation

3 public questions tagged with this topic.

Lipid Link Protein

What type of bond formation occurs in myristoylation?

Myristoylation represents cotranslational irreversible lipidation catalyzed by cytosolic N-myristoyltransferases NMT1 and NMT2. After methionine aminopeptidase removes initiator methionine, glycine at position two becomes exposed as acceptor. NMT binds myristoyl-CoA, a fourteen-carbon saturated fatty acyl thioester, and transfers acyl chain to alpha-amino group of N-terminal glycine forming stable amide linkage resistant to neutral hydroxylamine, alkaline treatment, and reducing agents, unlike labile thioesters. The myristate provides approximately eight kilocalories per mol hydrophobic insertion energy insufficient alone for permanent anchoring, so second signals are required including polybasic cluster that binds acidic phospholipids or secondary palmitoylation of adjacent cysteines. Consensus sequence MGXXXS/T directs recognition for substrates like Src family kinases, ADP-ribosylation factor, G-alpha i subunits, and MARCKS. Myristate targets proteins to cytosolic leaflet microdomains regulating membrane-cytosol shuttling, signal transduction, vesicular trafficking and oncogenic transformation with high membrane specificity. Additional regulation involves myristoyl electrostatic switch where calcium binding exposes myristate in recoverin and MARCKS modulating membrane binding cycles.

Ref: Lodish et al., Molecular Cell Biology, 9th ed., Chapter 10, Protein Lipidation and Myristoylation.

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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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Lipid Link Protein

Which amino acid is commonly involved in myristoylation?

N-myristoylation is co-translational irreversible modification attaching 14-carbon saturated fatty acid myristate from myristoyl-CoA to target protein. N-myristoyltransferase NMT recognizes N-terminal sequence Met-Gly-X-X-X-Ser/Thr after methionine aminopeptidase removes initiator methionine, exposing glycine at position 2 for amide bond formation. The glycine requirement is absolute; replacement with other residues abolishes myristoylation. Myristate anchor provides weak membrane affinity that often cooperates with additional palmitoylation or polybasic cluster to stably tether proteins to inner leaflet of plasma membrane, Golgi and endomembranes. Src family kinases, MARCKS, recoverin and many viral proteins utilize myristoylation for membrane localization required for signal transduction, vesicular trafficking and assembly. Serine, cysteine and tyrosine are not acceptor sites for myristoylation; serine can be phosphorylated, cysteine palmitoylated or prenylated, and tyrosine sulfated or phosphorylated, highlighting glycine specificity that defines this lipid modification pathway in eukaryotes and some bacteria. 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: Resh, Biochim Biophys Acta 1999, N-myristoylation mechanisms; Farah et al., J Biol Chem 2020, NMT specificity.

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