Association of NMT2 with the acyl-CoA carrier ACBD6 protects the N-myristoyltransferase reaction from palmitoyl-CoA

Soupène, Eric; Kao, Joseph P. Y.; Cheng, Daniel H.; Wang, Derek; Greninger, Alexander L.; Knudsen, Giselle M.; DeRisi, Joseph L.; Kuypers, Frans A.

doi:10.1194/jlr.m065003

Cited by 21 publications

(43 citation statements)

References 62 publications

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“…This type of delivery system has been shown to operate for enzymes involved in β-oxidation and glycerolipid synthesis[13] . Another option is illustrated by the recent finding that NMT2 can bind to an Acyl-CoA binding domain containing protein, ACBD6, and this interaction prevents binding of palmitoyl-CoA to NMT2[14]. It has yet to be determined whether this mechanism, which has been demonstrated in vitro , is operative in cells.…”

Section: N-myristoylationmentioning

confidence: 99%

Fatty acylation of proteins: The long and the short of it

Resh

2016

Progress in Lipid Research

237

235

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Long, short and medium chain fatty acids are covalently attached to hundreds of proteins. Each fatty acid confers distinct biochemical properties, enabling fatty acylation to regulate intracellular trafficking, subcellular localization, protein-protein and protein-lipid interactions. Myristate and palmitate represent the most common fatty acid modifying groups. New insights into how fatty acylation reactions are catalyzed, and how fatty acylation regulates protein structure and function continue to emerge. Myristate is typically linked to an N-terminal glycine, but recent studies reveal that lysines can also be myristoylated. Enzymes that remove N-terminal myristoyl-glycine or myristate from lysines have now been identified. DHHC proteins catalyze S-palmitoylation, but the mechanisms that regulate substrate recognition by individual DHHC family members remain to be determined. New studies continue to reveal thioesterases that remove palmitate from S-acylated proteins. Another area of rapid expansion is fatty acylation of the secreted proteins Hedgehog, Wnt and Ghrelin, by Hhat, Porcupine and GOAT, respectively. Understanding how these membrane bound O-acyl transferases recognize their protein and fatty acyl CoA substrates is an active area of investigation, and is punctuated by the finding that these enzymes are potential drug targets in human diseases.

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Section: N-myristoylationmentioning

confidence: 99%

Fatty acylation of proteins: The long and the short of it

Resh

2016

Progress in Lipid Research

237

235

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“…ACBD6 stimulates myristoyl-peptide formation and protects the activity of the human NMT2 and protozoan Plasmodium NMT enzymes from competition by other acyl-CoAs ( Fig 3A) [29,30]. The ANK module is not necessary for acyl-CoA binding (Fig 2) but all the recombinant forms lacking this module failed to stimulate and to protect NMT ( Fig 3A).…”

Section: The C-terminal Module Protects Nmt From Competitionmentioning

confidence: 99%

“…Details of the various truncations and chimeras are presented in Fig 1. DSS (disuccinimidyl suberate; ThermoFisherScientific) crosslinking experiments were performed as previously described [29]. NMT2 (10μM) and the linker.ANK (30μM) recombinant proteins were mixed in 10μl and dialyzed at 4˚C for 16 hours in 100mM sodium phosphate pH 8.0, 150mM sodium chloride and 0.3% (w/v) CHAPS.…”

Section: Protein Production and N-myristoyltransferase Activity Measumentioning

confidence: 99%

“…In the absence of a mechanism protecting NMT from competitive inhibition, the greater abundance of other acyl-CoA, such as C 16 -CoA, would prevent access of the substrate. The human acyl-CoA binding protein ACBD6 interacts with the human (NMT1 and NMT2) and the protozoan Plasmodium falciparum NMT enzymes and, protects their activity [29,30]. The P. falciparum ACBD6 protein also regulates activity of PfNMT [30].…”

Section: Introductionmentioning

confidence: 99%

“…The P. falciparum ACBD6 protein also regulates activity of PfNMT [30]. In the NMT2 / ACBD6 complex, the acyl-CoA carrier allows C 14 -CoA to reach NMT binding site, even in the presence of excess concentration of C 16 -CoA and C 12 -CoA [29,30]. The binding activity and the NMT-stimulatory properties of the acyl-CoA binding (ACB) domain and of the ANK-repeat motifs (ANK module) of ACBD6 were determined in this study.…”

Section: Introductionmentioning

confidence: 99%

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Requirement of the acyl-CoA carrier ACBD6 in myristoylation of proteins: Activation by ligand binding and protein interaction

Soupène¹,

Schatz

Rudnik‐Schöneborn

et al. 2020

PLoS ONE

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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. Skinderived 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.

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Neurogenetics, Genome-Wide Association and Candidate Gene Studies

Haller

2020

Neurobiopsychosocial Perspectives on Aggression and Violence

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Association of NMT2 with the acyl-CoA carrier ACBD6 protects the N-myristoyltransferase reaction from palmitoyl-CoA

Cited by 21 publications

References 62 publications

Fatty acylation of proteins: The long and the short of it

Fatty acylation of proteins: The long and the short of it

Requirement of the acyl-CoA carrier ACBD6 in myristoylation of proteins: Activation by ligand binding and protein interaction

Neurogenetics, Genome-Wide Association and Candidate Gene Studies

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