Abstract
Glycine N-myristoylation is an essential acylation modification modulating the functions, stability, and membrane association of diverse cytosolic proteins in human cells. Myristoyl-CoA is the 14-carbon acyl donor of the acyltransferase reaction. Acyl-CoAs of a chain length compatible with the binding site of the N-myristoyltransferase enzymes (NMT) are competitive inhibitors, and the mechanism protecting these enzymes from unwanted acyl-CoA species requires the acyl-CoA binding protein ACBD6. The acyl-CoA binding domain (ACB) and the ankyrin-repeat motifs (ANK) of ACBD6 can perform their functions independently. Interaction of ANK with human NMT2 was necessary and sufficient to provide protection. Fusion of the ANK module to the acyl-CoA binding protein ACBD1 was sufficient to confer the NMT-stimulatory property of ACBD6 to the chimera. The ACB domain is dispensable and sequestration of the competitor was not the basis for NMT2 protection. Acyl-CoAs bound to ACB modulate the function of the ANK module and act as positive effector of the allosteric activation of the enzyme. The functional relevance of homozygous mutations in ACBD6 gene, which have not been associated with a disease so far, is presented. Skin-derived fibroblasts of two unrelated individuals with neurodevelopmental disorder and carrying loss of function mutations in the ACBD6 gene were deficient in protein N-myristoylation. These cells were sensitive to substrate analog competing for myristoyl-CoA binding to NMT. These findings account for the requirement of an ANK-containing acyl-CoA binding protein in the cellular mechanism protecting the NMT enzymes and establish that in human cells, ACBD6 supports the N-myristoylation of proteins.
Highlights
Myristoylation of proteins is the irreversible covalent attachment of the C14 tail of myristoylCoA to an N-terminal glycine
The acyl-CoA binding domain (ACB) domain of ACBD6 is sufficient for acyl-CoA binding [33] and the ankyrin-repeat motifs (ANK) domain is sufficient for interaction, stimulation and protection of N-myristoyltransferase enzymes (NMT)
Interaction of peroxisomal ACBD5 with VAPB does not require the ACB domain [41] but a form truncated of the domain could not restore normal level of β–oxidation of very-long-chain fatty acids in an ACBD5 KO cell [42]
Summary
Myristoylation of proteins is the irreversible covalent attachment of the C14 tail of myristoylCoA to an N-terminal glycine. The hydrophobicity of the C14 tail is not strong enough to force membrane association of myristoylated-proteins [3,6,14]. Change in location can affect the functions of the myristoylated-proteins as well as of the cytosolic and membrane proteins interacting with them [1,3,4,6,7,15]. An electrostatic switch induced by phosphorylation weakens interaction of a basic cluster to the membrane and results in the release of myristoylated-MARCKS in the cytosol [16]. Myristoylated proteins can be targeted by proteases liberating soluble peptide of altered function [19] and proteolytic products of non-myristoylated proteins can become myristoylated following the exposure of an internal glycine within a myristoylation recognition motif [20]. The IpaJ protease of Shigella flexneri cleaves the myristoylated-glycine of the host proteins, such as Golgi-associated ARF/ARL family GTPases [21,22]
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